68391:
Herbal Medications: An Evidence-Based Review

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Overview

Patients, and in some cases healthcare providers as well, are not fully aware of the
health risks incurred by ingestion of herbal medications, either due to their potential
adverse effects or pharmacological interactions with other medications. This situation is
further compounded by the fact that at least 60% of the patients taking herbal medications
do not disclose this fact to their healthcare provider. This course provides the knowledge
and tools required for clinicians to discuss natural health products with patients and other
members of the healthcare team. It also discusses the need for psychologists to actively
inquire if the patient is taking herbal medications and take this information into account.
A brief historical background and an overview of regulatory bodies responsible for
overseeing herbal medications is provided. Relevant examples of widely used herbal compounds
are presented. Clinically relevant information on commonly used herbal medications regarding
therapeutic effectiveness, pharmacological mechanism of action, adverse effects and drug
interactions are reviewed based on scientific evidence.

Education Category Alternative Medicine

Release Date 07/01/2013

Expiration Date 06/30/2016

Audience

Considering the widespread availability and increased use of herbal medications, this
introductory course is designed for psychologists whose clients use herbal
medications.

Accreditations & Approvals

NetCE is approved by the American Psychological Association to sponsor continuing education for psychologists. NetCE maintains responsibility for this program and its content.

Designations of Credit

NetCE designates this continuing education activity for 10 credit(s).

Course Objective

Considering the pharmacological interactions between herbal medications (HMs) and
conventional medications, it is paramount to increase the awareness and knowledge of
healthcare professionals about HMs. The purpose of this course is to increase psychologists'
awareness of the potential risks and benefits of HMs from an evidence-based perspective and
promote the planned inclusion of HM use in patients' history. This course should allow
psychologists to discuss HMs in a knowledgeable and succinct manner with patients and
colleagues.

Learning Objectives

Upon completion of this course, you should be able to:

Discuss the prevalent current and historical use of HMs in North America.

Explain the need to inquire about the use of HMs during preparation of a patient's medical history, including components of a culturally sensitive assessment.

Describe the differences between the process of development and approval of HMs versus conventional medications, and the implications of health claims and therapeutic efficacy of HMs.

Outline the merits and limitations associated with the application of contemporary scientific principles and methodologies (i.e., evidence-based medicine) to assess the efficacy and safety of HMs.

Discuss, based on scientific and conventional medical principles, the pharmacological properties, efficacy, safety, toxicology, therapeutic indications, and recommended dosages of saw palmetto and St. John's wort.

Describe the potential risks and benefits of ginkgo.

Identify key characteristics of ginseng.

Discuss the use of echinacea and kava, including potential adverse effects.

Review the use of garlic and valerian as HMs.

Outline the potential medical uses of andrographis and English ivy leaf.

Analyze the available evidence for the use of peppermint, ginger, soy, and chamomile.

Faculty

A. José Lança, MD, PhD, received his Medical Degree at the University of Coimbra in Coimbra, Portugal, and completed his internship at the University Hospital, Coimbra. He received his PhD in Neurosciences from a joint program between the Faculties of Medicine of the University of Coimbra, Portugal, and the University of Toronto, Toronto, Canada. He was a Gulbenkian Foundation Scholar and received a Young Investigator Award by the American Brain & Behavior Research Foundation.

Dr. Lança participated in international courses and conferences on neurosciences. He has contributed to a better understanding of the mechanisms underlying the ontogenetic development of the brain opiatergic system. As a research scientist at the Addiction Research Foundation (ARF) in Toronto, he initiated research on the functional role played by dopaminergic cell transplants on alcohol consumption, leading to the publication of the first research reports on cell transplantation and modulation of an addictive behavior. Subsequently, he also investigated the role played by other neurotransmitter systems in the limbic system and mechanisms of reward, co-expression of classical neurotransmitters and neuropeptides and potential role in neuropsychiatric disorders.

He is an Assistant Professor in the Department of Pharmacology at the Faculty of Medicine and at the Faculty of Dentistry at the University of Toronto, where he lectures and directs several undergraduate and postgraduate pharmacology and clinical pharmacology courses. He was the Program Director for Undergraduate Studies in the Department of Pharmacology of the University of Toronto. He has developed clinical pharmacology courses for the Medical Radiation Sciences and Chiropody Programs of The Michener Institute for Health Sciences at the University of Toronto.

Dr. Lança’s commitment to medical education started while a medical student, teaching in the Department of Histology and Embryology, where he became cross-appointed after graduation. In Toronto, he has contributed extensively to curriculum development and teaching of pharmacology to undergraduate, graduate, and medical students.

He has authored research and continuing education in peer-reviewed publications and is the author of six chapters in pharmacology textbooks. Dr. Lança has conducted research in various areas including neuropharmacology, pharmacology of alcoholism and drug addiction, and herbal medications.

He has developed and taught courses and seminars in continuing medical education and continuing dental education. His commitment to continuing education emphasizes an interdisciplinary approach to clinical pharmacology.

Faculty Disclosure

Division Planner

James Trent, PhD

Division Planner Disclosure

The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

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68391:
Herbal Medications: An Evidence-Based Review

DEFINITIONS

The National Center for Complementary and Alternative Medicine (NCCAM), a division of the
U.S. National Institutes of Health, defines complementary and alternative medicine (CAM) as "a
group of diverse medical and healthcare systems, practices, and products that are not
generally considered part of conventional medicine" [1]. CAM includes a wide range of products including natural health products
(NHPs) and practices such as prayer, chiropractic, homeopathy, and massage therapy. In Canada,
a similar definition is followed, and regulation of NHPs falls under the jurisdiction of the
National Health Products Directorate, a branch of Health Canada [2].

Herbal medications (HMs), also known as phytochemicals or botanical medications, are
considered an integral part of dietary supplements in the United States or natural health
products in Canada [3]. Dietary supplements
also include other natural compounds, such as vitamins, minerals, amino acids, and essential
fatty oils [2].

PREVALENCE OF HERBAL MEDICATION USE

The desire to maintain and promote individual health has
contributed to the prevalent use of natural health products, including herbal medications. In
2007, approximately 4 out of 10 adults (38.3%) in the United States had used CAM in the past
year [4,5].

In Canada, an estimated 11% of the population takes HMs [6]. Data from the National Center for Health
Statistics indicates that supplement use among U.S. adults 20 years of age and older increased
from 42% (as reported in the National Health and Nutrition Examination Study [NHANES] III) to
50% during the period 2003–2006, with use more common among women than men [5]. Nonvitamin,
nonmineral natural products are the most commonly used category of CAM, followed by deep
breathing, meditation, and massage therapy [5]. The NCCAM also found that approximately 12% of children 17 years of age or younger use
some form of CAM [5]. Considering the aging of
the "baby-boom" generation and increased incidence of chronic health issues, it is likely that
the use of CAM, and HMs in particular, will increase in this group.

The use of CAM for general health and well-being is greater in people with higher
education and income, rather than in individuals with lower education and lower socioeconomic
status [7]. However, the 2002 Centers for
Disease Control and Prevention National Health Interview Survey revealed that poor adults were
more likely to use megavitamin therapy and prayer specifically for a health reason than not
poor adults [8]. An estimated 13% of adult CAM
users indicated that they used CAM because conventional medicine was too expensive [8].

It is particularly relevant for medical practitioners that several studies have shown that
more than 50% of patients who require conventional health care use CAMs separately or in
conjunction with conventional therapies [7,9,10]. A published study of men with prostate cancer revealed that one-third of
the patients used CAM in conjunction with their conventional therapy [11]. Of those, approximately 30% were taking
vitamin and mineral supplements, while 40% were taking herbal compounds either alone or in
conjunction with vitamins and antioxidants [11]. It has been estimated that 50% to 70% of patients using CAM fail to disclose this
information to physicians or other healthcare professionals [9]. Patients are more likely to disclose CAM use if it is provider-based
rather than self-care use [7].

The prevalent use of herbal medications is particularly
relevant to medical practice for three main reasons. First, it is commonly and erroneously
assumed by patients that by being natural the compound is intrinsically beneficial and devoid
of adverse effects. Second, patients often neglect to report to their physicians and other
healthcare providers that they are taking HMs, as they think that it is not relevant. Third,
pharmacological interactions between compounds, regardless of whether they are from herbal or
conventional origin, may alter therapeutic efficacies and cause negative interactions or
serious adverse effects.

It is therefore essential to increase awareness regarding these issues and evaluate the
pharmacological profile and therapeutic properties of the most commonly used herbal
medications based on scientific evidence, including clinical trials.

HISTORICAL OVERVIEW OF HERBAL MEDICATIONS IN NORTH AMERICA

Chemical compounds extracted from plants, animals, or
micro-organisms, either in raw or purified form, have been used to treat disease for centuries
and even millennia. Many of these substances are essential therapeutic tools and widely used
in conventional medicine. Aspirin, digitalis, reserpine, morphine, most antibiotics, and
anticancer drugs, to name but a few, are perfect examples of the long historical transition
between natural medications and mainstream or conventional Western medications. The
introduction of new and more effective conventional medications, such as statins, a class of
drugs that inhibit 5-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase activity and
effectively lower hyperlipidemia, and the antimalarial drug artemisinin, are pertinent
examples of identification, extraction, and pharmaceutical application of natural compounds
[12,13]. In fact, it has been estimated that approximately 25% to 50% of marketed
drugs are derived from natural products [14].
One review found that almost 50% of the new small-molecule drugs introduced between 1981 and
2002 were natural products or their chemical derivatives [13]. Consequently, the difference between NHPs/HMs and conventional Western
medications is not solely or primarily based on the origin of the compound (i.e., natural
versus synthetic) but rather on the process of scientific evaluation of the pharmacological
and biological properties, toxicological profile, and therapeutic efficacy of a particular
compound prior to its approval for marketing. In Western countries, the process of approval of
new conventional drugs is tightly regulated. It falls under the jurisdiction of the Food and
Drug Administration (FDA) in the United States; in Canada, it is regulated by Health
Canada.

In the United States, herbal medications are considered
dietary supplements and are regulated by the Dietary Supplement Health and Education Act
(DSHEA) of 1994 [3]. Under this legislation,
some claims, including structure and function, may be made by the manufacturer without
requiring proof of safety and efficacy needed for conventional FDA-regulated medications. The
product may be advertised as beneficial to maintaining or improving health of a particular
organ or system, and the DSHEA states that the manufacturer is responsible for the safety of
herbal products [3]. It is, however, the
responsibility of the FDA to prove that an herbal compound is unsafe before a product is
removed from the market [15]. This has been
the case regarding the sale of dietary supplements, including HMs, containing ephedrine
alkaloids (e.g., ephedra), which were prohibited in the United States by the FDA in April 2004
[16].

In Canada, herbal medications are classified as natural health products and fall under the
jurisdiction of the Natural Health Products Regulations [17]. Canadian regulations provide a regulatory framework similar to the one
existing in the United States. It is Health Canada's mandate to regulate the sale and safety
of HMs, as illustrated by the ban on products containing ephedra in quantities greater than 8
mg per dose, 32 mg per day, or at any dose in combination with other stimulants, including
caffeine.

MEDICAL AND PATIENT PERCEPTIONS AND MISCONCEPTIONS ON THE USE OF HERBAL
MEDICATIONS

The pharmacology, therapeutic properties, and toxicological
potential of herbal medications are often the object of inaccurate and biased assessment.
Numerous factors contribute to this situation. In some cases, healthcare providers may have
limited formal training in the area, which can result in a limited appreciation of the
beneficial properties of some phytochemicals and of their potential health risks, including
pharmacological interactions with conventional medications [18]. A survey of community pharmacists in Texas showed that in spite of the
fact that 70% of new patients use CAM, pharmacists rarely ask patients about CAM use. This is
a particularly troublesome occurrence considering the role played by the pharmacist in
assessing potential interactions with conventional drugs [19].

A 2010 United Kingdom-based Drug and
Therapeutics Bulletin (DTB) survey of 164 healthcare professionals, consisting
mostly of hospital physicians and general practitioners, found that while a majority of
physician participants (75.3%) considered HMs to be helpful in some circumstances, 72%
indicated that the general public had misplaced faith in HMs and 86% felt the general public
was poorly informed about HMs [20].

Patients often use herbal compounds based on the
misconception that due to being natural, these products are intrinsically beneficial, do not
cause adverse effects, and are devoid of any serious toxicological potential. This is a
widespread and inaccurate assessment. Patients need a better understanding of why informing
their healthcare providers about CAM, and especially HM, use will be beneficial to their
health.

In response to the increasing interest in CAM, including HMs, the U.S. Federation of State
Medical Boards has approved guidelines for the use of CAM in conventional medical practice.
This document provides information regarding "clinically and ethically responsible use of CAM,
within the boundaries of professional practice and accepted standard of care," and provides
the methodology to evaluate physicians' adherence to standards of medical practice required by
state legislation [21].

CULTURALLY SENSITIVE ASSESSMENT

Because the use of CAM, including HMs, may be tied closely to cultural or ethnic
traditions, it is important that any assessment for use of these products be undertaken with
an understanding of possible barriers to disclosure. Pachter developed a dynamic model to
facilitate culturally sensitive assessments, which involves several tiers and transactions
[22]. The first component of Pachter's
model calls for the practitioner to take responsibility for cultural awareness and
knowledge. The professional should be willing to acknowledge that he/she does not possess
enough or adequate knowledge in health beliefs and practices among the different ethnic and
cultural groups he/she comes in contact with. Reading and becoming familiar with medical
anthropology is a good first step.

The second component emphasizes the need for specifically tailored assessment [22]. Pachter advocates the notion that there is
tremendous diversity within groups. For example, one cannot automatically assume that a
Nigerian immigrant adheres to traditional beliefs. Often, there are many variables, such as
level of acculturation, age at immigration, educational level, and socioeconomic status,
that influence health ideologies. Finally, the third component involves a negotiation
process between the patient and the professional [22]. The negotiation consists of a dialogue that involves a genuine respect
of beliefs. The professional might recommend a combination of CAM and Western treatments. A
knowledge of HMs commonly used in different cultures may allow healthcare professionals the
opportunity to ask questions about specific products, as many patients do not volunteer
information regarding their use of HMs.

DISCLOSURE AND CLINICAL NEED TO IDENTIFY THE USE OF HERBAL MEDICATIONS

As noted, an estimated 50% to 70% of the patients fail to
report the use of HMs to their physicians and other healthcare providers [9,11]. Some patients assume that reporting CAM use is not relevant because they
are not mainstream medical products or procedures. In one literature review, the major reason
for patients' failure to disclose the use of CAM was their concern of a negative reaction by
the practitioner [9]. In the same study, lack
of interest or assumed lack of knowledge by the medical practitioner were also reported among
the main reasons for nondisclosure. This is supported by the 2010 DTB survey, which indicated
that 0% of the 164 responding physicians felt that their personal knowledge about HMs was
"very good;" only 1.8% believed that physicians in general were "well informed" about HMs, and
89% conceded that their knowledge of herbal medications was "much poorer" than their knowledge
of prescription drugs [20].

A number of patients do not disclose the use of HMs simply because their healthcare
provider did not inquire [9]. While 77% of
physicians worry that their patients may not be informing them about HM use, the DTB survey
found that 9% never ask about HM use, 47% occasionally ask, 27% ask most of the time, and only
13% always ask [20]. Thus, considering the
prevalent use and the common perception of healthcare professionals' attitudes toward herbal
medications, it is essential to change these practices in order to safeguard patients'
health.

CLINICALLY RELEVANT PHARMACOLOGY AND TOXICOLOGY OF HERBAL MEDICATIONS

In North America, regulation of HMs is not as strict as that
applied to conventional medications. In fact, good manufacturing practices applicable to food
manufacturing are the only regulations in place to assure standards and quality control [23]. The concentration of active ingredients in
HMs, however, is affected by numerous factors, including [9,24,25,26]:

The correct identification of the botanical source

The presence of contaminants or substitution of the intended source for other plants
of lower cost with potential toxicological consequences

Growing conditions, including temperature, geography and time of harvest, and possible
contamination with micro-organisms, heavy metals, pesticides, or prescription drugs

Collection of the appropriate plant part (e.g., leaves versus root)

Preparation of specimens (e.g., drying, grinding)

Laboratory processing (e.g., solvent used for extraction of active ingredients)

Storage

Formulation of the final product (e.g., liquid versus solid pill)

These processes vary considerably among manufacturers and influence product quality and
concentration of active ingredients in the final product.

Unlike conventional medications, herbal products have numerous active ingredients.
Pharmacological and chemical interactions between ingredients may be required for the product
to be effective. Accordingly, isolation and purification of a single individual chemical may
not lead to the same therapeutic effect as the one described for the original product.

PHARMACOKINETICS

Pharmacokinetics is the study of the effects exerted on
drugs by the body, namely the processes of drug absorption, distribution, biotransformation,
and ultimate elimination of drugs and their metabolites. All drugs ingested for nutritional,
therapeutic, preventive, or diagnostic purposes, regardless of being of natural or synthetic
origin, undergo processes of absorption and eventual distribution throughout body tissues
and systems prior to reaching their molecular target. Drug distribution does not occur
homogeneously throughout the body. Effective availability and concentration of a drug in
different organs and tissues is influenced not only by the chemical properties of the drug
(e.g., molecular size, electrical charge, ability to bind to plasma proteins, affinity for
transporters that will carry the drugs across cell membranes) but also by the anatomical and
histological properties of the tissues themselves (e.g., degree of vascularization and type
of capillaries present, including the tightly sealed blood-brain barrier).

Subsequently, all drugs undergo chemical transformation by the body. Briefly, drug
transformation is carried out by enzymes leading to the production of metabolites that are
either water-soluble (hydrophilic) and excreted mainly through the kidney, or lipid-soluble
(hydrophobic). The latter are further metabolized in the liver mainly by a large family of
enzymes known as cytochrome P450 (CYP450). Selective CYP450 isoforms, such as CYP3A4 and
CYP3A5, are particularly relevant for clinical practice. In fact, CYP3A4 and CYP3A5 account
for the metabolism of about 50% of all known drugs. For example, drugs such as digoxin,
warfarin, indinavir, cyclosporine A, statins, and some calcium channel antagonists and
anticonvulsants are metabolized by these isoforms. Increases or decreases in CYP450 activity
therefore influence the processes of drug transformation, alter drug availability, and can
have serious clinical implications [27].

PHARMACODYNAMICS

The pharmacological and therapeutic properties of HMs and conventional medications
result from the biological interaction between an active compound and its target. The
mechanisms underlying the drug-target interactions are studied in pharmacodynamics. The
precise molecular mechanisms underlying the actions of HMs are, however, more difficult to
establish due to the complex composition and presence of numerous chemical elements. For the
most commonly used HMs, certain chemical elements have been isolated, their effects studied
in vitro, and their therapeutic properties clinically evaluated. Allicin, for example, has
been identified as the chemical ingredient in garlic responsible for its cardioprotective
and plasma lipid-lowering properties. This effect correlates with the inhibition of HMG-CoA
reductase by allicin and other disulfides present in garlic, which is a mechanism of action
shared with statins [28,29,30].

The beneficial effects of saw palmetto in the treatment of benign prostatic hyperplasia
(BPH) have been obtained with standardized lipidosterolic extracts. Several mechanisms of
action have been reported, in both in vitro and in vivo models. Although saw palmetto has
alpha 1-adrenoceptor antagonistic properties, a mechanism of action common to tamsulosin
(Flomax), and anti-inflammatory properties because it inhibits cyclooxygenase, its
beneficial effects on BPH correlate with its inhibition of 5-alpha-reductase. This latter
mechanism is shared with the conventional drugs finasteride (Proscar) and dutasteride
(Avodart) [31,32].

DRUG INTERACTIONS

Drug-drug interactions, herb-drug interactions, and food-drug interactions can occur
when different compounds are concurrently present in the body. These interactions can be
either of a pharmacokinetic nature (i.e., absorption, distribution, metabolism, excretion)
or a pharmacodynamic nature (i.e., interfering with the interaction between the drug and its
molecular target, such as a receptor). Rarely, both pharmacokinetic and pharmacodynamic
interactions may occur at the same time.

The complex composition of HMs can, in principle, become
the source of various interactions. Multiple chemical compounds can interact either
synergistically (i.e., increase the activity of one or more of its chemical constituents) or
antagonistically (i.e., decrease the activity of one or more of its components).
Furthermore, herbal remedies may include complex mixtures of several herbs, thereby
significantly increasing the number of active compounds in the preparation. This makes it
particularly difficult to ascertain which of the chemicals is pharmacologically responsible
for a particular biological event. The co-administration of HMs and conventional drugs
further increases the possibility of interactions, which can be manifested during
experimental conditions or clinically.

Herb-drug interactions apparently occur less frequently and are less serious than
drug-drug interactions. This is due to the weaker potency of the herbal medications;
however, interactions and adverse events may also be under-reported and relevant information
may not be collected [33,34].

Pharmacokinetic Interactions

Pharmacokinetic interactions between chemical compounds can alter the therapeutic
properties of a drug and either increase or decrease the effectiveness of one or both
compounds. For example, compounds in grapefruit and grapefruit juice strongly inhibit the
liver enzyme CYP3A4 in a dose-dependent manner, thus reducing or preventing the
biotransformation of drugs metabolized by this enzyme. This leads to abnormally high and
potentially serious or lethal concentrations of these drugs in the blood [33]. Some clinically relevant interactions
take place when grapefruit (as well as some other citrus varieties, primarily sour types)
are administered with statins, anxiolytic drugs, methadone, or calcium channel blockers
[35]. This interaction has led to a ban
of grapefruit products in many healthcare facilities.

Goldenseal, used topically as an antiseptic and systemically for the treatment of
gastrointestinal disorders and menstrual pain, is also known to strongly inhibit CYP3A4,
which prevents the metabolism of drugs such as erythromycin, leading to abnormally high
blood levels of this antibiotic [36,37].

An opposite effect is caused by other medications, including the herbal antidepressant
St. John's wort (SJW). SJW induces both CYP3A4 and the intestinal drug transporter
P-glycoprotein. Consequently, drugs transformed by CYP3A4 will be degraded faster and
their blood levels quickly fall below therapeutic levels with foreseeable clinical
implications [34]. These mechanisms have
been linked to the low circulating levels of the antirejection drug cyclosporine in
patients who received a kidney transplant and were also being treated with SJW [34]. A similar mechanism was reported in a
heart transplant recipient and was responsible for the acute rejection of the transplant
[38].

Other pharmacokinetic interactions between SJW and prescription drugs have been the
subject of several clinical studies, including one that reported the interaction with the
anxiolytic alprazolam [39]. Alprazolam is
metabolized by CYP3A4 in the liver and intestinal mucosa, and SJW induced the activity of
CYP3A4, shortening the elimination half-life of alprazolam from 12.4 to 6 hours.

Pharmacodynamic Interactions

Pharmacodynamic drug-drug or herb-drug interactions result from actions on molecular
targets that mediate different processes of a physiological response. The final result of
these interactions can lead to an increase (i.e., synergism or potentiation) or decrease
(i.e., inhibition or offset) of the expected response. For example, the antidepressant
properties of SJW are associated with hypericin, pseudohypericin, and hyperforin. These
compounds have a mechanism of action identical to fluoxetine (Prozac) and paroxetine
(Paxil), and inhibit serotonin reuptake [40]. It is therefore not surprising that SJW, like the selective serotonin reuptake
inhibitors, has a pharmacodynamic synergistic interaction with drugs that further
contribute to increases in serotonin concentration in the synapse, such as monoamine
oxidase (MAO) inhibitors (e.g., phenelzine) [39,41,42]. The abnormal increase of serotonin
resulting from the herb-drug interaction can cause a mild "serotonin syndrome,"
characterized by confusion, restlessness, high blood pressure, fever, and muscle spasms
[43,44,45,46].

Clinically relevant interactions also occur between HMs and conventional medications
that affect hemostasis, such as antiplatelet drugs (e.g., acetylsalicylic acid,
dipyridamole), anticoagulants (e.g., heparin and vitamin K antagonists such as warfarin),
and fibrinolytic drugs (e.g., alteplase, reteplase). A number of HMs contain high amounts
of coumarin, salicylates, or other compounds that interfere with hemostasis. Both red
clover (Trifolium pretense) and sweet clover (Melilotus alba) are rich in coumarin. Mold contamination of
these plants converts the coumarin into dicoumarol, the vitamin K antagonist from which
the potent anticoagulant warfarin is derived. Toxicity has been reported in cattle grazing
on moldy clover hay [47,48,49]. Although this interaction has not been reported in humans, due to the
below-threshold effect of dicoumarol when the herb is administered at the recommended
dosage, it is advisable to closely monitor hemostasis in patients undergoing anticoagulant
therapy [48,49].

Another potential herb-drug interaction exists between ginkgo biloba and conventional
anticoagulants, as a few cases of hemorrhage have been reported in the literature. One
German study, however, has shown that the inhibition of the platelet-activating factor by
ginkgo biloba was only observed for amounts at least 100 times higher than the recommended
dose [50]. Although, mechanistically,
there is the potential for synergistic interaction between ginkgo biloba and
anticoagulants, it seems unlikely. Interactions between various HMs and conventional
cardiovascular pharmacotherapy, such as anticoagulants, antihypertensives, diuretics,
statins, and digoxin, have been reported [51].

ADVERSE EFFECTS/ADVERSE DRUG REACTIONS

As previously discussed, the pharmacological properties of
HMs and their interactions with prescription drugs can cause adverse effects, also known as
adverse drug reactions, and have the potential to cause toxicological effects. The reporting
of adverse effects is the most important tool in post-marketing drug surveillance and
accounts for 60% of the data used for adverse effects assessment [52,53]. In the United States, the FDA has the FDA Adverse Event Reporting
System (FAERS). Adverse event reporting for dietary supplements, including HMs, should be
directed to FDA's MedWatch. The equivalent agency in Canada is the Canada Vigilance Adverse
Reaction Online Database. Reports should be made to MedEffect Canada. An adverse events
reporting system, Natural Medicines Watch, has also been established by the Therapeutic
Research Faculty, an independent publisher of evidence-based recommendations for
pharmaceuticals (Resources) [54].

In both the United States and Canada, adverse effects can
also be reported to the manufacturer. In turn, the manufacturer should submit all the
collected information to the regulatory agencies. The efficiency of this latter process,
however, has been the subject of lengthy debate.

TOXICOLOGY OF HERBAL MEDICATIONS

Systematic analysis of the evidence-based toxicological
properties of HMs is scarce. Toxicological effects of HMs can result from:

Administration of a high dose of an HM and consequent abnormal exacerbation of the
intended therapeutic effect or occurrence of a toxic effect unrelated to the original
therapeutic effect

Adulteration of the product either by contamination with other plants or with
prescription medications illegally included in the product

Interactions with conventional drugs or other HMs

There is a relationship between the administered amount of a drug and the effect
obtained (dose-response curve). As for any drug, very low doses of HMs, below the intended
therapeutic threshold, do not have a pharmacological effect, whereas higher doses within the
therapeutic range will elicit the intended effect (therapeutic dose). Above therapeutic
doses, the compound may elicit unintended responses, which can result from the exacerbation
of the therapeutic effect and the accompanying adverse effects. For example, high doses of
an antihypertensive drug can cause abnormally low blood pressure. Alternately, it may stem
from the occurrence of another adverse effect not directly related to the primary
therapeutic action of the drug. Acetaminophen, the leading cause of acute liver failure in
the United States, is a typical example to illustrate the latter type of event [55]. When administered at doses above the
therapeutic threshold for analgesia and antipyresis, it causes liver toxicity and can
eventually cause death due to liver failure. The smallest dose of a drug that elicits a
toxic effect is known as the minimum toxic dose. The lowest drug dose that causes death is
known as the minimum lethal dose.

Considering the fact that HMs have a complex and varied chemical composition, and due to
the limited knowledge of the precise effects on different constituents of organ systems,
healthcare providers should always be aware of their potential toxicity. A relevant example
results from chronic ingestion of germander (Teucrium
chamaedrys). In traditional Chinese medicine, it is used in the form of tea or
extract for a variety of purposes, including weight loss. A number of germander-induced
cases of severe hepatotoxicity have been reported in the scientific literature, leading to
it being banned in France [56]. In 1996, two
more cases of hepatotoxicity were reported in Canada [57]. It has been established that its toxicity is caused by the development
of autoantibodies that cause immunoallergic hepatitis, and it is strongly advised that it
should not be ingested for any reason [58].

Toxicity may also occur as the result of adulteration in the composition of HMs. This
may occur by contamination with toxic plants or molds due to improper selection or storage.
Adulterations of the intended product may occur either accidentally or deliberately when
unscrupulous suppliers replace the intended plant for a cheaper one. Although this
substitution may cause physiological responses that resemble the ones intended, other
effects, including toxicity, may occur. Widely reported cases have occurred in several
countries, including the United States, where a mixture of plants used in traditional
Chinese medicine to detoxify the body contained Digitalis lanata instead of plantain and
caused digitalis intoxication in two patients. More numerous cases were prevented by the
timely intervention of the FDA, leading to the immediate recall of the product [59]. Another well-known case occurred in
Belgium, where more than 40 patients developed interstitial fibrosis and progressive renal
failure when the nephrotoxic herb, Aristolochia fangchi,
known to contain potent carcinogens, was substituted for the intended Stephania tetrandra[60].

On several occasions, it has been found that an HM was deliberately adulterated by
adding a prescription drug. Such was the case reported in England, when very high levels of
the synthetic drug dexamethasone were found in an herbal cream used to treat eczema [61]. In Saudi Arabia, a complete toxicological
screening of more than 200 samples of traditional products revealed contamination by
synthetic drugs (8 cases), micro-organisms (18 cases), toxic substances of natural origin
(14 cases), or high heavy metals content (39 cases) [62]. These examples illustrate the need for an increased public and
professional awareness, the implementation of appropriate quality control and exhaustive
testing of supplies, adherence by the manufacturers to good manufacturing practices, and
selection of products manufactured by reputable companies.

HERBAL MEDICATIONS: REGULATORY ASPECTS

COMPARISON OF THE PROCESSES OF APPROVAL OF HERBAL COMPOUNDS AND CONVENTIONAL
DRUGS

As mentioned, the main difference between HMs and conventional Western medications is
neither exclusively nor primarily based on the origin of the compound (i.e., natural versus
synthetic) but rather in the process of evaluation regarding efficacy and safety, which the
compound should undergo prior to being marketed. In fact, many conventional medications are
extracted from natural sources or are the chemical derivatives of naturally occurring
molecules.

In Western countries, the process of approval of new conventional medications is tightly
regulated. New drugs undergo a process of detailed scrutiny and scientific evaluation prior
to being released into the market. Briefly, during the preclinical stages, the
physiopathological mechanisms underlying the disease are identified, and biological targets
(e.g., enzyme, receptor, gene) are identified. Drugs aimed at biological targets are tested
in vitro, and in vivo experiments are conducted under controlled conditions. When the
potential therapeutic benefit has been established based on the preclinical studies and the
drug is considered ready for human studies, an elaborate application is then submitted to
the appropriate regulatory institution: the FDA in the United States and Health Canada in
Canada. The application includes:

Composition and source of the drug

Manufacturing information

Data from in vitro and animal studies

Detailed plans for proposed clinical trials

Names and credentials of physicians responsible for conducting the clinical
trials

If approved, human studies of the investigational new drug
(IND) can be initiated. At the institutional level, interdisciplinary review boards are
responsible for assuring the ethical and scientific integrity of the clinical trials.

Clinical studies are conducted in four stages or phases (I, II, III, and IV). Phase I is
aimed at establishing drug safety, dosage, and pharmacokinetic properties of the drug (e.g.,
half-life, metabolism). These are open or nonblind studies, in which both investigators and
healthy subjects (25 to 100) know what is being administered. Results of human studies are
compared with animal studies.

The goal of Phase II is to study the effect of the drug on
volunteer patients (100 to 200) with the disease for which the drug was developed. Subjects
will either receive the drug, a placebo (negative control), or the standard drug (positive
control) used in the treatment of the disease. Further toxicological studies in animals will
continue to assess chronic toxic potential.

Finally, in Phase III, double-blind or cross-over studies
are conducted to further evaluate the efficacy of the drug in larger groups of thousands of
patients. When Phase III is finished and if the results meet the goals initially
established, a new drug application (NDA) will be submitted to the FDA or its congener in
another country. After several years of preclinical research, 4 to 6 years of clinical
trials, and as many as 3 years after the NDA has been submitted, the FDA may then approve to
market the drug. At that point, Phase IV is initiated and a mechanism of post-marketing
surveillance, including reporting of adverse effects, will be in place.

Compared to this elaborate process of approval, the
mechanisms required for the marketing of HMs are extremely simple. To start, in many Western
countries, including the United States and Canada, herbal medications are not legally
considered drugs, but rather as dietary supplements and natural health products,
respectively. Consequently, HMs are not legally required to undergo extensive preclinical
investigation, and clinical trial evaluations are not required prior to the marketing of the
herbal product. Rather, approval is based on traditional usage.

It should be noted that several herbal medications, namely in the European community,
have been thoroughly evaluated, including safety and efficacy, product standardization, and
well-conducted clinical trials with comparison to standard treatments (i.e., Phase III).
These principles apply to the studies conducted to evaluate the efficacy of standardized
preparations of saw palmetto (Serenoa repens) in the
treatment of BPH [31,32,63].

In the United States and Canada, under the supervision of
the NCCAM and the National Health Products Directorate (NHPD), more stringent standards are
being developed, aimed at product standardization, detailed information of active
ingredients, reporting of adverse effects, product identification number, and future
development of product monographs. These regulations will contribute significantly toward an
evidence-based approach to herbal medicine.

SCIENTIFIC EVALUATION OF HERBAL MEDICATIONS

PRECLINICAL STUDIES AND EVALUATION IN CLINICAL TRIALS

The number of scientific studies aimed at unraveling the
mechanism of action of HMs has undergone a remarkable growth in the last 10 years.
Development of new legislation, availability of research funds to study the pharmacological
mechanisms of action and therapeutic efficacy of HMs, drug standardization, and
implementation of clinical trials to assess HMs have played a central role in the
development of an evidence-based approach to phytotherapeutics. The NCCAM in the United
States and the NHPD in Canada are pivotal in establishing advisory panels, coordinating
scientific resources and expertise, and funding quality research on HMs [64]. The American Society for Pharmacology and
Experimental Therapeutics has long supported the increase in the National Institutes of
Health's NCCAM budget for peer-reviewed research on botanical medications, particularly
aimed at studying mechanisms of action and interactions with prescription drugs [65].

Scientific evidence on HMs should also be included in the basic curriculum in medical,
pharmacy, dental, and nursing schools. Continuing education of healthcare professionals also
contributes to a multidisciplinary and inclusive evidence-based assessment of HMs as part of
a broader approach to maintenance of health and disease prevention.

IDENTIFICATION OF ACTIVE COMPOUNDS, ISOLATION, AND STANDARDIZATION

Standardization of the product and its individual chemical
constituents is of major importance, and reliability of practices and procedures by the
manufacturer is absolutely crucial. Several reports have analyzed the concentration of
active ingredients present in herbal medications and compared the values obtained with those
reported on the label by the manufacturer. Batch-to-batch variability has also been
reported, and in one particular case of a compound containing ephedrine and methyl
ephedrine, concentration of these substances varied by 180% and 1000%, respectively [66].

The lack of standardization may also account for negative results obtained in some
clinical trials [67]. One study revealed
that, in the case of the antidepressant SJW (Hypericum perforatum), the amount of two of its
most important chemical constituents, hypericin and pseudohypericin, can vary from 108% to
30% or even to as little as 0.1% of the amount reported on the label when a chemical
analysis is conducted in a large number of samples from various manufacturers [68].

More reassuring results have been reported. The chemical
composition of five of the most commonly used HMs was studied, and these results were
compared to the information provided in the label by the manufacturer [69]. Results of this study, conducted by the
University of California, Los Angeles (UCLA) Center for Human Nutrition, are encouraging and
reflect a positive trend in increased quality and standardization of HMs by the
manufacturers. For each product, 3 different samples from each of 12 bottles (6 bottles for
each of the 2 separate batches) were collected. Five of the most commonly used HMs in North
America were studied, specifically saw palmetto, SJW, echinacea, ginkgo biloba, and kava.
Samples were purchased from 8 to 10 different suppliers nationally available in the United
States. A greater consistency of composition was observed for samples purchased
over-the-counter than for those purchased by mail order. A drastic decrease in variability
of the marker compound was observed between batches; saw palmetto and SJW were the least
variable, and the most variable were ginseng and echinacea [69].

In fact, analysis of the saw palmetto specimens revealed
that the concentration of the marker compound ranged from 77% to 106%, and for two of the
manufacturers the values were within ±10% of their label claim. For SJW, the concentration
of the marker compound hypericin ranged from 88% to 110%, and for two of the suppliers it
was within ±10% of their claim. In the echinacea compounds studied, the concentration of the
marker compound ranged from 78% to 173% of the reported value, and two of the manufacturers
were within ±10% of the concentration claimed. Ginseng was the most variable HM, and the
amount of the marker varied from 44% to 261% of the claim. Only for one of the manufacturers
was the value within ±10% of the claim. For kava, the values were within ±10% of their claim
for more than 70% of the suppliers [69].

In the United States, the National Institute of Standards and Technology (NIST), in
collaboration with the National Institutes of Health Office of Dietary Supplements, the FDA,
the Center for Drug Evaluation and Research, and the Center for Food Safety and Applied
Nutrition, is developing procedures regarding the standardization of dietary supplements and
natural health products [70]. The
development of standardization of active ingredients, accurate evaluation of chemical
contaminants, such as toxic metals present in the soil and/or acquired during processing,
and screening for microbiological contaminants, such as Escherichia
coli, will certainly contribute to an increase in consumer reassurance, and to
the acceptance by larger numbers of conventional healthcare providers [71].

Legislation requiring the standardization of herbal medications has been successfully
implemented in several countries of the European Union, with benefits regarding the
scientific assessment of pharmacological properties and conduction of well-controlled
clinical trials and mandatory reporting of adverse effects [72]. It has often been argued that a stricter
control of phytochemicals further enhances their role as useful complementary rather than
alternative therapeutic tools to conventional medications.

EVIDENCE-BASED REVIEW OF THE MOST COMMONLY USED HERBAL MEDICATIONS

Considering the large number of available HMs, it is beyond the scope of this course to
exhaustively review them all. Fourteen of the most commonly sold HMs will be reviewed
following an evidence-based assessment of several parameters relevant to clinical practice
(Table 1). For each phytomedicine, the following subjects
will be presented:

Common name and scientific name

Historical and current use

Pharmacology

Evidence-based therapeutic use and effectiveness

Adverse effects and drug interactions

Toxicology

Dosage

The therapeutic effectiveness of each medication is based on published scientific data
regarding in vitro and in vivo studies of the mechanism of action and clinical studies,
including randomized clinical trials, clinical studies, and meta-analyses. Accordingly, each
herbal product is ranked into one of the following four categories:

★★E: Clinically Beneficial: Demonstrated by several
controlled clinical trials, although some studies show conflicting or inconclusive
results

★E: Limited effectiveness: Demonstrated by controlled
clinical trials

No E data: Nonexistent or minimal supporting scientific
evaluation

Product safety guidelines follow the same general rules applicable to mainstream drugs,
and use during pregnancy, lactation, and childhood should be restricted to compounds tested
for teratogenicity, carcinogenicity, and general toxicity. Otherwise, it is not advisable for
the patient to be exposed to an untested HM. As a guideline, a product is ranked as:

SAW PALMETTO

Efficacy: ★★E

Safety: S

Common Name and Scientific Name

Saw palmetto (Serenoa repens or Sabal serrulata) is also known as American dwarf palm or
cabbage palm. This abundant and scrubby palm is indigenous to Florida and other
southeastern states of the United States.

Historical and Current Use

Saw palmetto berries collected in the autumn were used by southeastern Native
Americans in the treatment of urinary disorders and as an antiseptic. Saw palmetto
extracts are now used in the treatment of BPH. In several European countries, use of this
herb has been approved for the treatment of mild-to-moderate BPH. In Germany and Austria,
saw palmetto is the most common form of therapy for BPH and represents more than 90% of
all drugs prescribed for the treatment of this disorder [49,63].

Pharmacology

The beneficial effects of standardized liposterolic
extracts (phytosterols) in the treatment of BPH are now well established. The extracts
represent 85% to 95% of free fatty acids from saw palmetto berries. Although the mechanism
of action of saw palmetto is not completely understood, both in vitro and in vivo studies
have revealed that the beta-sitosterol component of the extract correlates with its
efficacy in the treatment of BPH [73,74,75]. Saw palmetto inhibits 5-alpha-reductase, the enzyme responsible for
the transformation of testosterone into dihydrotestosterone (DHT), its tissue-active form
[75,76]. This mechanism of action is similar to the one described for
finasteride and dutasteride [32,75,77]. It should be noted, however, that finasteride only inhibits the type
1 isoform of 5-alpha-reductase responsible for the production of different testosterone
metabolites in the tissues, whereas saw palmetto inhibits both type 1 and type 2 isoforms
[75,78].

Other pharmacological mechanisms of action of saw
palmetto have been reported in the literature, namely that it competes with DHT and blocks
androgen receptor stimulation, although this mechanism does not seem to correlate with its
clinical efficacy [75,79]. In vitro, saw palmetto extracts have
alpha-1 adrenoceptor blocking properties like the standard drug tamsulosin, albeit this
mechanism does not seem to account for saw palmetto's therapeutic effects as it is not
observed at the lower concentrations, which are equivalent to the doses used in humans
[80]. Interestingly, saw palmetto also
inhibits cell proliferation and promotes apoptosis (i.e., programmed cell death) of
prostate cancer cells, and its anti-inflammatory properties have been linked to its
inhibitory actions on cyclooxygenase and lipoxygenase [81,82,83]. Together, all of these mechanisms may
synergistically contribute to the therapeutic efficacy of saw palmetto extracts.

Evidence-Based Therapeutic Use and Effectiveness

According to the American Urological Association, at this time, the
available data do not suggest that saw palmetto has a clinically meaningful effect on
lower urinary tract symptoms secondary to benign prostatic hyperplasia. Further clinical
trials are in progress, and the results of these studies will elucidate the potential
value of saw palmetto extracts in the management of patients with benign prostatic
hyperplasia.

The clinical effectiveness of saw palmetto in the treatment of mild-to-moderate BPH
has been extensively studied. A comprehensive review of clinical studies that assessed the
efficacy of saw palmetto versus placebo and saw palmetto versus finasteride was published
in 2002 [63]. Results from 21 clinical
trials, with a total of more than 3000 patients, were analyzed. Several clinical
parameters were evaluated, including urinary symptoms (e.g., dysuria, fullness, bladder
residual volume), nocturia, urine flow rate, and prostate size (Boyarsky, American
Urologic Association Score, and International Prostate Symptom Score). The authors
concluded that, "men taking saw palmetto were nearly twice as likely to report improvement
in symptoms than men taking placebo," [63]. Also, "when compared to finasteride, saw palmetto provided similar responses in
urologic symptoms and flow measures and was associated with a lower rate of impotence"
[63]. This review, however, lacks
information regarding comparisons between saw palmetto and alpha-1 adrenoceptor
antagonists such as tamsulosin. Updates of this review, published in 2009 and 2012, found
that saw palmetto was not more effective than placebo for treatment of urinary symptoms
consistent with BPH [84,85].

A large study of more than 2500 patients suffering from mild-to-moderate BPH compared
the effectiveness of saw palmetto versus tamsulosin (704 patients), saw palmetto versus
finasteride (1098 patients), and two different doses of saw palmetto (160 mg twice a day
versus saw palmetto 320 mg once a day) [32]. The study demonstrated a better outcome for patients taking saw palmetto than those
taking either of the conventional drugs. Also, unlike the conventional drugs, no negative
impact on sexual function was reported by patients treated with saw palmetto. These
results further support other well-conducted studies [77,86,87,88,89,90,91,92]. Interestingly,
saw palmetto was less effective than finasteride in reducing prostate volume, although
involution of the prostate epithelium and reduction of inflammation was observed [32,93]. Co-administration of saw palmetto and finasteride did not improve the
treatment outcome. A report in which saw palmetto efficacy was not observed may be
attributable to the study being conducted in patients with moderate-to-severe BPH, as
opposed to the beneficial effects on patients with a mild-to-moderate condition [94]. In addition to the population cohort
difference, the study also failed to conduct an appropriate dose-response study or raise
the dose of saw palmetto to adjust for the severity of the medical condition.

In conclusion, evidence demonstrates that saw palmetto is effective in the treatment
of mild-to-moderate BPH, is less expensive, and is better tolerated than conventional
medications [87,95]. In addition, it is now well established
that saw palmetto does not interfere with the laboratory measurements of prostate specific
antigen (PSA), used to assess the progression of prostate cancer [76,96]. This presents a considerable advantage over 5-alpha-reductase
inhibitors finasteride and dutasteride, which are known to mask PSA readings and prevent
an accurate assessment of the disease progression and concurrent development of prostate
cancer [76,96]. The efficacy of saw palmetto in the
treatment of more severe BPH has not been established.

Saw palmetto has also been used to treat other genitourinary disorders, including
chronic prostatitis. However, clinical studies have shown a lack of significant
improvement in patients treated with saw palmetto for 1 year, contrasting with the
benefits observed in the group treated with finasteride [95,97].

It has also been advocated that saw palmetto, either alone or in conjunction with
other nutraceuticals, may also play an important role in the prevention of BPH, although
the results obtained are inconclusive [98]. The effects of chronic saw palmetto administration on the organization of chromatin
structure in patients with BPH provides an insight of the molecular effects of saw
palmetto potentially relevant to gene expression and tissue differentiation [99].

Adverse Effects and Drug Interactions

Consistently, all studies revealed the absence of significant side effects. A 2008
meta-analysis of saw palmetto trials found that serious adverse effects (e.g., cancer,
sexual dysfunction, hepatotoxicity, respiratory problems) were no more common in treatment
groups than in placebo groups [100].
Gastrointestinal symptoms, including nausea or abdominal pain, may occur in less than 2%
of patients but seem to decrease when doses are taken with a meal. Because of its
antiandrogenic properties, women should not take saw palmetto for treatment of urogenital
problems if they take contraceptives, hormone replacement therapy, have breast cancer, or
are pregnant [63,75]. Furthermore, there is no clinical
evidence supporting a beneficial effect of saw palmetto in the treatment of urethritis in
women. Interactions with anticoagulants are negligible and arise from a single reported
case [101]. In clinical trials, 3% of the
subjects developed hypertension, compared to 2% treated with finasteride; however, this
difference was not statistically significant [77].

Toxicology

Saw palmetto is widely considered a safe phytomedicine, and no serious toxicological
effects are reported in the scientific literature [100].

Dosage

Standardized lipophilic extracts of saw palmetto are administered at a dose between
100–400 mg twice daily for the treatment of BPH [31,32,49,75]. A dose of 160 mg twice a day is the most commonly used dosage in
clinical trials [75]. Therapeutic benefits
are observed within 3 to 4 weeks after the initiation of treatment, which usually lasts
for 3 to 6 months.

ST. JOHN'S WORT

Efficacy: ★★E

Safety: AEs/DIs

Common Name and Scientific Name

St. John's wort (Hypericum perforatum) is also
known as amber touch-and-heal, goatweed, and klamath weed.

Historical and Current Use

This perennial, native to Europe, Western Asia, and North Africa, is a resilient weed,
widespread in parts of the United States and southern Canada. The plant has golden-yellow
flowers that bloom in the summer, which are collected and dried. The medicinal use of SJW
as a topical anti-inflammatory and for wound healing has been known since ancient Greece.
Extracts have been used in folk medicine for the treatment of depression and other mood
disorders and also as a diuretic. Today, SJW is used primarily for the treatment of
mild-to-moderate depression and is the most commonly prescribed antidepressant in Germany,
where it is available as a prescription medication [72,102].

Pharmacology

Several chemicals, including naphthodianthrones (e.g., hypericin, pseudohypericin),
phloroglucinols (e.g., hyperforin), flavonoids (e.g., quercetin), and essential oils, are
the primary constituents of SJW [103].
Formulations are standardized to concentrations of hypericin, usually 0.3% to 0.4%, which
is considered the active ingredient responsible for the antidepressant properties of SJW.
Clinical and pharmacological studies, however, have shown that hyperforin concentrations
of 2% to 4% correlate closely with antidepressant efficacy [104,105].

The pharmacological mechanisms of action of SJW extracts
relevant to its antidepressant effect are complex. Hypericin may have a minor role in MAO
inhibition, a mechanism shared with the classical antidepressant phenelzine [75]. This mechanism, however, is not
considered clinically significant because it is only observed at concentrations 100 times
higher than those used to treat depression [31]. Hyperforin is generally agreed to be the active component [75]. Both hypericin and hyperforin inhibit
synaptic reuptake of serotonin, which is the same action as fluoxetine and paroxetine, but
they also inhibit the reuptake of dopamine and noradrenaline, like other antidepressants
including venlafaxine [106].

After a single dose, the half-life of hypericin is 4 to 6 hours, whereas after chronic
administration, the half-life of hypericin is 1 to 2 days [107,108]. These values are comparable to those observed for fluoxetine (1 to 3
days) and the selective serotonin re-uptake inhibitor (SSRI) paroxetine (12 hours) [46].

Long-term administration of SJW extracts increase the synaptic density of serotonin
receptors by 50%, whereas the receptor affinity remains unchanged [109]. The increase in number of serotonin
receptors was observed after a minimum 10 to 12 days treatment, a time frame that
correlates with the well-known therapeutic delay of standard antidepressant drugs [110]. Together, the increased number of
serotonin receptors and the increase in synaptic concentrations of neurotransmitters
provide a mechanistic explanation for the antidepressant effects of SJW [103,107,111].

SJW extracts also have antibacterial properties, accounting for the antiseptic and
wound-healing properties of topical formulations. Hyperforin is effective in inhibiting
gram-positive bacteria, including penicillin-resistant and methicillin-resistant Staphylococcus aureus, but it is not effective against
gram-negative bacteria. One randomized trial showed the effectiveness of SJW topical
application in the treatment of atopic dermatitis [112,113,114].

Some in vitro studies have shown that SJW extracts have antiviral properties, namely
against influenza virus, and one study has identified a novel protein in SJW that
suppresses gene expression in human immunodeficiency virus (HIV) [112,115]. However, a Phase I clinical trial provided negative results [116]. It is important to emphasize that SJW
should not be administered to HIV or acquired immune deficiency syndrome (AIDS) patients
because of the pharmacokinetic interactions with antiretroviral protease inhibitors, such
as indinavir, saquinavir, and ritonavir, and non-nucleoside reverse transcriptase
inhibitors, such as efavirenz, which are metabolized by CYP3A4. Induction of CYP3A4 by SJW
drastically reduces drug concentrations in the blood by 50% to 80% with subsequent loss of
HIV suppression [117].

Finally, in vitro studies have shown that hyperforin and hypericin inhibit tumor cell
growth by induction of apoptosis [118,119]. Although these compounds seem
to have high efficacy, their potential clinical usefulness as anticancer agents is, at
this point, merely speculative.

Evidence-Based Therapeutic Use and Effectiveness

Several clinical trials have assessed the efficacy and safety of SJW preparations in
the treatment of depression. A 2005 Cochrane Review extensively analyzed published
randomized, double-blind trials comparing SJW with placebo (26 studies) or with standard
antidepressants (14 studies) [120]. SJW
was demonstrated to be "more effective than placebo and similarly effective as standard
antidepressants for treating mild-to-moderate depressive symptoms" [120]. The treatment period lasted from 4 to
12 weeks.

Two large clinical trials, one of which was sponsored by NCCAM, conducted in the
United States did not support these findings [121,122]. Both studies
were conducted on patients who suffered from moderate-to-severe depression, and many
patents presented with a history of drug-resistant depression, which may have affected the
outcomes. The Hypericum Depression Trial Study Group has also been criticized because the
response rates for both the SJW-treated and the sertraline-treated groups were not
different from the placebo-treated group. In another randomized study, conducted in
Germany, the effect of SJW (900 mg/day standardized SJW extract) on moderate-to-severe
depression was compared with paroxetine (20 mg/day) [40]. The treatment was continued for 6 weeks, and in initial
non-responders, after 2 weeks of treatment the doses were increased by 100%. The results
indicated that, in the treatment of moderate-to-severe depression, hypericum extract was,
"at least as effective as paroxetine" and was better tolerated [40]. A 2008 Cochrane Review of trials
examining the treatment of severe depression with hypericum reached similar conclusions as
to its efficacy in comparison to placebo and conventional antidepressants. Also, subjects
in the SJW groups had a lower drop-out rate, possibly due to fewer side effects [123].

It is established in the scientific literature that standardized SJW extracts are
effective and safe in the treatment of mild-to-severe depression [49,112,120,123,124,125].

Adverse Effects and Drug Interactions

Although there is evidence that St. John's wort may be of benefit in
mild or moderate depression, the National Collaborating Centre for Mental Health
recommends that practitioners not prescribe or advise its use by people with depression
because of uncertainty about appropriate doses, persistence of effect, variation in the
nature of preparations, and potential serious interactions with other drugs (including
oral contraceptives, anticoagulants, and anticonvulsants).

SJW is well-tolerated and generally safe. Mild side effects include gastrointestinal
symptoms, mild sedation or tiredness, dizziness, headache, and dry mouth. Incidence of
side effects in SJW-treated patients (4% to 12%) is similar to that observed in the
placebo-treated group and significantly lower than standard antidepressants [49,75,126,127]. Two rare adverse events may occur after
administration of SJW. First, transient photosensitivity may occur when administered in
higher doses, and second, the occurrence of a serotonin syndrome when co-administered with
SSRIs is possible [128]. The latter
results from the synergistic interaction between the drugs raising serotonin to abnormally
high levels [43,44,45,46,129].

Pharmacokinetic interactions with SJW are rare and only occur at higher doses.
Induction of cytochrome P450 isoforms, namely CYP3A4 and CYP1A2, by SJW results in a
decreased bioavailability of drugs metabolized by this liver enzyme. These drugs include
the immunosuppressant cyclosporine, the anticoagulant warfarin (bleeding), oral
contraceptives (causing breakthrough bleeding), antiretroviral protease inhibitors, and
theophylline [34,49,117,125]. A report has
also shown a reduction in plasma levels of the HMG-CoA reductase inhibitor simvastatin
[130]. Activation of the intestinal
P-glycoprotein transporter also accounts for the reduction in plasma concentrations of
digoxin [117].

In conclusion, although SJW has consistently been reported to be a safe drug when
administered within its therapeutic range, its potential interactions with other drugs or
herbs (e.g., kava) require caution and a thorough investigation during patient interview
prior to use.

Toxicology

It is widely accepted in the literature that, when used within the normal therapeutic
range, SJW is devoid of toxicological properties. In high doses, SJW can elicit
photosensitivity. Phototoxicity results from light-induced transformation of
hypericin-derived pigments and has been reported in HIV patients receiving high doses of
intravenously-administered SJW [116]. To
date, only one study of potential teratogenicity during human pregnancy has been
conducted, with data collected from the pregnancies of 54 SJW-treated women and 108 women
either treated with conventional antidepressants or receiving no pharmacologic treatment.
Rates of fetal malformations were similar among the three test groups and similar to rates
of malformations in the general population; additionally, premature and live birth rates
among the three test groups were similar [131]. Further research in this area is needed, and SJW administration in
pregnant patients should therefore be avoided [75].

Dosage

Standardized preparations of SJW are usually administered from 500–1800 mg per day
[49,112,120,124,125]. In most studies, 900 mg was administered daily (450 mg twice a day,
or 300 mg three times a day) [75].

GINKGO

Efficacy: ★★E

Safety: S

Common Name and Scientific Name

Ginkgo (Ginkgo biloba), also known as kew tree, ginkyo, or duck-foot tree (because of
the characteristic fan-shaped leaves), is a large, resilient and long-living tree
cultivated by monks in China, where many individual specimens are documented to be more
than 1000 years old. Ginkgo trees, often known as living fossils, are the only survivors
of the entire Ginkgoaceae family. Fossils of this tree that date back more than 200
million years have been identified in areas throughout the Northern Hemisphere, including
Europe and North America. Ginkgo trees were brought into Japan and other East Asian
countries around 1200 C.E., possibly in relation to the spread of Buddhism. In the
seventeenth century, they were reintroduced in Europe and, more recently, in North
America. Ginkgo is a resilient tree to parasites and diseases and, interestingly, also
survived the Hiroshima atomic bombing.

Historical and Current Use

The designation originates from ginkgo, meaning silver apricot, and biloba, which
describes the two-lobed shape of the leaf. Historically, leaf extracts have been used in
traditional Chinese medicine to treat a variety of disorders, including asthma, allergies,
premenstrual syndrome, tinnitus, cognitive impairments resulting from aging and dementia,
and vascular diseases including central and peripheral vascular insufficiencies.
Standardized leaf extracts are used based on their neuroprotective and vascular regulatory
properties in the management of intermittent claudication, age-related memory loss,
dementia, and early stages of Alzheimer's disease [31,132]. Plum-like fruits
of the female tree are not edible and cause contact dermatitis. Ingestion of the seeds
causes headache, nausea, diarrhea, and even seizures when ingested in larger amounts [49,133].

Pharmacology

More than 40 chemical components of ginkgo have been isolated, including flavonoids,
terpenoids, flavones, catechins, sterols, and organic acids. The two most important and
active groups of chemicals are the flavonoids, such as quercetin and kaempferol, and the
terpenoids, including ginkgolides A, B, C, J, and M and bilobalide. Ginkgo biloba extracts
available in Europe and North America are standardized to 24% flavonoids and 6% terpenoids
and have been used in hundreds of in vitro and in vivo studies and numerous clinical
trials [31,49].

The biological properties of ginkgo biloba extract result from the complex
interactions among chemical components, and it is therefore difficult to establish a
well-defined cause-effect relationship between specific elements and biological effect.
Nevertheless, it is now well established that flavonoids have antioxidant and free-radical
scavenger properties. They also have a protective effect against apoptosis and
beta-amyloid neurotoxicity of Alzheimer's disease and may play an important role in the
prevention of neuronal degeneration in Parkinson's disease [134,135].

Ginkgo biloba extract also stimulates receptor expression and neurotransmitter
concentrations in the brain, particularly acetylcholine [136,137,138,139]. This latter mechanism of action is
similar to the cognitive enhancer, tacrine, previously used in the treatment of
Alzheimer's disease [140].

Evidence-Based Therapeutic Use and Effectiveness

There is scientific evidence supporting the beneficial
use of standardized ginkgo biloba extract, 120–240 mg/day, in the treatment of
mild-to-moderate cognitive impairment, such as age-related dementia, multi-infarct
dementia, and Alzheimer's disease [31,141,142]. Some studies show that ginkgo biloba
extract is as effective as the acetylcholinesterase inhibitor donepezil (Aricept) in the
treatment of patients with early stages of Alzheimer's disease, although these findings
are not supported by additional studies [143]. Although studies have shown that ginkgo biloba extract improves
cognitive functions in older healthy individuals, the findings should be confirmed by
larger clinical trials [31,144,145,146,147].

Clinical trials have assessed the effectiveness of
ginkgo biloba extract in the treatment of cerebral insufficiency, which is a syndrome
combining mild cognitive impairment, headaches, confusion, poor concentration, fatigue,
and dizziness, and is associated with mood disorders. Long-term treatment with ginkgo
biloba extract at 120–150 mg/day reduced symptoms and improved short-term memory [148,149].

Some evidence supports the effectiveness of ginkgo
biloba extract in the treatment of peripheral vascular disorders, including intermittent
claudication and, to a lesser degree, Raynaud's syndrome [31,150]. In fact, one clinical trial demonstrated that ginkgo biloba extract
is as effective as pentoxifylline, the standard medication for the treatment of
intermittent claudication [151]. However,
a 2008 analysis concluded that while ginkgo biloba treatment did slightly increase
treadmill walking time of participants with peripheral artery disease and led to a slight
reduction of pain, the therapy produced only modest overall improvements [152].

The beneficial effects of ginkgo biloba extract in a
variety of medical conditions, such as tinnitus and cochlear disorders, and vascular
retinopathies, including macular degeneration, have also been reported in the scientific
literature, although larger studies are required to confirm the clinical outcome. It is
possible that in these conditions, ginkgo biloba extract is the most effective when
administered in conjunction with standard therapies.

Adverse Effects and Drug Interactions

Consistently, ginkgo biloba extract is considered a safe
and well-tolerated drug when used at the recommended dose for periods of up to 6 months.
In most clinical studies, the incidence of adverse effects is similar to placebo. Less
than 2% of patients develop side effects, namely headache, nausea, or mild
gastrointestinal symptoms [49]. Two cases
of subarachnoid bleeding have been reported in patients taking ginkgo biloba extract and
warfarin, and one case of subarachnoid bleeding and intraocular hemorrhage has also been
reported in a patient taking ginkgo biloba extract and acetylsalicylic acid concurrently.
A case of postoperative bleeding has also been reported after laparoscopic surgery [153]. In these cases, however, the causal
relationship between ginkgo biloba extract and bleeding was not clearly established.
Furthermore, bleeding was not reported in any of the clinical trials involving hundreds of
thousands of subjects [49]. Nonetheless,
it is advisable to discontinue ginkgo biloba extract administration several days prior to
surgery [75].

Toxicology

Although in vivo studies did not report either
embryotoxic or teratogenic effects of ginkgo biloba extract, this phytomedicine should be
avoided during pregnancy and breastfeeding [31,75,154]. As mentioned, severe contact
dermatitis, similar to that caused by poison ivy, can result from direct contact with the
pulp of ginkgo fruit of the female tree. Ingestion of ginkgo seeds, but not leaves, in
large amounts (50 or more) causes headache, nausea, diarrhea, and even seizures. This
condition is known in Japan as gin-nan[75,133]. Pollen from the male tree can
be allergenic for sensitive individuals [49].

Dosage

Standardized extracts are administered at a daily dose of 120–240 mg, in two or three
equal doses, for periods of 6 months or longer [31,75,141,142].

GINSENG

Efficacy: ★E

Safety: No S
data

Common Name and Scientific Name

Ginseng is a designation that applies to an HM that is prepared from the root of
different plants of the Araliaceae family. Asian
ginseng is obtained from Panax ginseng, American or
Canadian from P. quinquefolius, and Japanese from
P. japonicus. Siberian (Russian) ginseng is obtained
from the root of Eleutherococcus senticosus, a plant
that, although a member of the same Araliaceae family,
is not a member of the Panax genus, and hence, is not
considered a true ginseng. High-quality ginseng root is harvested in the autumn from
plants that are 5 to 6 years old.

Historical and Current Use

The name Panax is
derived from the Greek panacea, meaning cure-all. True to its etymology, the root of the
plant has been historically used for a variety of purposes, such as improvement of
cognitive and physical performance (i.e., ergogenic effect), cardiovascular diseases
(e.g., hypertension), diabetes, cancer, immunomodulation, and menopause. Evidence-based
knowledge regarding ginseng's medicinal properties is limited and has generally failed to
support historical claims, possibly with the exception of clinical trials assessing the
hypoglycemic properties of ginseng [31,155,156,157].

Pharmacology

Several chemicals, including polysaccharides (e.g.,
ginsan, ginsenans) and a variety of saponins known as ginsenosides, are found in ginseng
[75]. Ginsenosides, the most important
bioactive compounds, are complex molecules with a steroidal skeleton and modified side
chains. The concentration of different ginsenosides varies among species, age of plant,
and season of harvest and contributes to the limited understanding of the pharmacological
and physiological properties of each compound [75].

Ginsenosides Rb1, Rg1, and Rg2 improve cognitive performance, a mechanism likely
related to the stimulation of cholinergic activity implicated in the mechanisms of
learning and memory [75,158,159]. Both in vitro and in vivo models of Parkinson's disease have shown
that ginseng extracts have a neuroprotective effect against
1-methyl-1-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in rodents [160].

In vitro and in vivo studies have demonstrated that
ginseng polysaccharide GH1 and ginsenosides Rb2 and Re effectively reduce hyperglycemia
and liver glycogen in genetically obese mice as well as in nondiabetic and type 2 diabetic
patients [155,161,162]. Ginseng also stimulates insulin synthesis and release, an effect
possibly caused by the increase in nitric oxide production by ginseng [163]. Preliminary results suggest that
ginseng also regulates intestinal absorption of glucose and glycosylation of hemoglobin
A1c (HbA1c) [156]. If these results are
confirmed, ginseng may become a useful pharmacological tool in the prevention and
treatment of type 2 diabetes.

In vitro studies have shown that ginsenosides cause vasodilation and lower blood
pressure and that panaxynol, a potent inhibitor of thromboxane A2, prevents platelet
aggregation [164,165]. However, further scientific evidence of
the antihypertensive effects of ginseng is required prior to considering its potential
benefits in cardiovascular diseases.

The immunostimulatory and antiproliferative properties
of ginseng have also been reported in the scientific literature, but further studies are
required [166]. Ginseng has been studied
for use in the treatment of menopause symptoms, due to the steroid-like chemical
composition of ginsenosides, but the results were inconclusive.

Evidence-Based Therapeutic Use and Effectiveness

A Cochrane Review has concluded that the beneficial effects of ginseng preparations
were "not established beyond reasonable doubt" [159]. Other literature reviews, however, have reported that ginseng
extracts effectively reduced blood glucose levels in patients with type 2 diabetes,
although information regarding dosage and long-term effects is still incomplete [31,156]. A modest improvement in cognitive performance has also been reported
[31,156].

Adverse Effects and Drug Interactions

Ginseng preparations are generally well tolerated when administered within the
recommended dosage, and the available animal and human studies suggest that it is safe
[75]. As a result of its hypoglycemic
properties, it should be used cautiously in patients with type 2 diabetes concurrently
treated with oral hypoglycemic drugs.

Anticoagulant properties may also account for a few reports of epistaxis and vaginal
bleeding. In contrast, a randomized, controlled clinical trial has shown that ginseng
increases the risk of blood clotting in patients treated with warfarin. This
pharmacokinetic interaction occurs only after long-term administration of ginseng and
results from the induction of hepatic CYP450 isoforms responsible for warfarin metabolism
[167].

Interactions between ginseng and MAO inhibitors have also been reported and may cause
headaches, insomnia, nervousness, and mood disorders. Pharmacokinetic (e.g., CYP450
induction) and pharmacodynamic potentiation of antihypertensive drugs have also been
reported, and it should not be administered to hypertensive patients [31,75].

A few case reports describe the occurrence of diarrhea, unstable mood, skin rash, or
itching after long-term administration. Ginseng has also been associated with loss of
menstrual periods and vaginal bleeding in menopausal women. Therefore, ginseng should not
be administered to patients with hormone-sensitive conditions, such as breast or uterine
cancer and endometriosis [75]. In men, it
may be associated with estrogen-like effects, such as reduced libido and gynecomastia
[31].

Toxicology

At normal doses, ginseng is reported in the literature as being safe. Nevertheless,
ginseng should be avoided during pregnancy and breastfeeding [31,75,124]. A case of
reversible masculinization of a newborn girl when a mother allegedly took Eleutherococcus senticosus (Siberian ginseng) during pregnancy
has been reported [168]. In fact, it
resulted from the adulteration of the original product and substitution of Periploca sepium, a vine of the milkweed family, for ginseng.
Periploca sepium has been used in traditional Chinese
medicine for its stimulatory and libido enhancing effects. Accordingly, it should be
emphasized that the mentioned report has been erroneously used as published evidence of
ginseng toxicity [169,170]. Pediatric safety concerns regarding
ginseng treatment for upper respiratory tract infections were addressed in a 2008 Canadian
trial involving 75 subjects (3 to 12 years of age) given standard doses, low doses, or
placebo. The treatments were well tolerated, considered safe, and warrant additional
research for use on these and other types of pediatric infections [171].

Dosage

Purified ginseng extracts are generally standardized to 4% or 7% ginsenoside contents.
Usually, 100–200 mg of standardized 4% extract is administered orally once or twice daily,
for as many as 12 weeks [75]. In
traditional Chinese medicine, 0.5–2 g/day of dried ginseng root, equivalent to 200–600 mg
of standardized extract, is commonly used. Long-term administration of ginseng should not
exceed 1 g/day of the dry root form or 400 mg/day in the extract form. It is administered
daily for 2 to 3 weeks, then discontinued for 1 to 2 weeks. This treatment schedule may be
repeated for several months [31,124].

ECHINACEA

Efficacy: ★★E

Safety: S

Common Name and Scientific Name

The designation echinacea applies to several plants of
the Asteraceae/Compositae family, including E. angustifolia, E. pallida,
and E. purpurea. Echinacea, also known as coneflower,
narrow-leafed cone-flower, or black-eyed Susan, is indigenous to North America. It adapts
well and thrives in temperate climates, including Europe and Asia, where it has been
planted for decorative and medicinal purposes.

Historical and Current Use

Echinacea was used by Native Americans for a wide
variety of conditions, including chewing the roots for toothaches and gingivitis, root and
leaf infusion for stomach pain, colds, and infections, and topically as a disinfectant and
for wound healing. The use of echinacea was quickly adopted by early European settlers,
and shortly thereafter, it became widely used by European herbalists and physicians. In
Germany, it has been commonly used in mainstream medicine for almost a century. The German
Commission E has approved the use of echinacea for the amelioration of common-cold
symptoms, upper respiratory infections, and urinary tract infections, as well as topical
administration for treatment of superficial wounds [172]. The scientific literature generally supports a beneficial effect of
echinacea extracts in the treatment of cold symptoms, but evidence of its efficacy in the
prevention of colds is still limited [173]. Echinacea is the most widely sold HM in the United States and is the third most
popular natural product overall (surpassed only by fish oil and glucosamine) [8].

Pharmacology

Preparations from different portions (e.g., root, leaves) of the echinacea plants
(e.g., E. angustifolia, E.
purpurea, E. pallida) are collected during
the blooming season. The products are usually dried, and several chemical components,
namely caffeic acid derivatives (e.g., echinacosides, cichoric acid derivatives),
flavonoids (e.g., quercetin), alkylamides, and polysaccharides, are identified upon
alcoholic extraction [49]. Laboratory
analysis of echinacea extracts with high-pressure liquid chromatography provides the
chemical fingerprint of different echinacea species. In fact, in E. purpurea, no echinacosides are detected, whereas they are abundant in
E. angustifolia and E.
pallida. On the other hand, the amount of cichoric acid present in E. purpurea is forty- to sixty-fold higher than that present in
E. angustifolia and E.
pallida, respectively [174].
The relative concentration of various chemicals within the same species also varies in
different plant parts. Echinacoside concentrations are higher in the root, whereas
cichoric acid concentrations are higher in the flower of all echinacea species than in
other plant parts.

Due to its complex chemical makeup, the precise pharmacological and therapeutic
properties of each compound remain to be determined. Naturally occurring phenols, such as
the caffeic acid derivatives, are potent antioxidants due to the presence of hydroxyl
groups on aromatic rings that scavenge tissue-damaging free radicals [174]. In vitro experiments revealed that
alkylamides from echinacea inhibit cyclooxygenase and 5-lypoxygenase, accounting for its
anti-inflammatory properties [175,176].

The immunostimulatory properties of echinacea have been demonstrated both in vitro and
in vivo. Nonspecific effects, such as macrophage proliferation, stimulation of
interleukin-1, tumor necrosis factor, and interferon stimulation, as well as specific
effects, such as increase in numbers of T lymphocytes and natural killer cells, have been
reported in several studies [31]. Because
the total immunostimulatory effect of echinacea in humans remains to be established, the
German Commission E discourages the use of echinacea in patients with autoimmune
diseases.

Many preparations are standardized to 4% to 5% echinacosides, while others also report
the concentration of cichoric acid. A detailed study conducted by investigators from the
University of Colorado Health Sciences Center analyzed 59 samples of echinacea-only
preparations purchased from 11 retail outlets in the Denver area [177]. Ten percent of the samples did not
contain measurable amounts of echinacea, and the species content only agreed with the
label in 52% of the cases. Twenty-one preparations claimed to be standardized, but only
nine met the composition reported on the label. Although the efficacy of echinacea in the
treatment of some medical conditions has been reasonably established, the lack of species
identification and standardization, as well as product contamination/adulteration, should
be thoroughly investigated prior to being administered. The poor quality of many available
products certainly contributes to, or may account for, the conflicting results and
significant number of negative reports published in the scientific journals.

Evidence-Based Therapeutic Use and Effectiveness

The therapeutic effectiveness of echinacea preparations in prevention and treatment of
the common cold has been extensively studied. Several extensive reviews and meta-analysis
studies have been published, and some have provided conflicting or inconclusive
results.

According to the Institute for Clinical Systems Improvement, findings
in the medical literature do not support the use of echinacea in preventing viral upper
respiratory infection. Some preliminary data indicate that echinacea may shorten the
course of viral upper respiratory infection; however, studies that produced this data
are small. Methods by which echinacea is prepared are not standardized, and actual dose
delivered by specific products varies widely.

Level of Evidence: A and B
(Randomized, controlled trial and cohort study)

Researchers evaluated the therapeutic effectiveness of echinacea in the treatment of
the common cold based on 9 placebo-controlled clinical trials and concluded that its
effectiveness has not been established [178].

A Cochrane Review also evaluated the effects of echinacea on naturally-acquired colds
[179]. Sixteen of the 58 published
trials met their inclusion criteria. In the treatment of colds, echinacea was effective in
most clinical trials (9) and beneficial or marginally better than the placebo group in one
trial. In the remaining 6 clinical trials, no difference was observed between groups.
Interestingly, the authors also commented on the pervasive issue of lack of
standardization, the variability in bioactive composition of echinacea preparations, and
the likelihood that they may contribute to, or account for, the lack of consistency in
treatment outcomes.

Three randomized, double-blind, and placebo-controlled trials assessed the
effectiveness of echinacea on the avoidance of and severity of colds. Consistently, they
all revealed that subjects preventively treated with standardized echinacea extracts
acquired fewer colds (22%, 58%, 49%) than the placebo group (33%, 82%, 56%) [180,181,182]. However, due to
the small number of subjects studied in each trial, the decreases were not statistically
significant. A meta-analysis evaluated these three clinical trials, and due to the common
methodology used, the results of almost 400 subjects were combined [173]. The meta-analysis suggests that the
risk of developing a cold was 55% higher in the placebo than in the echinacea-treated
group, a statistically significant difference.

In vitro and in vivo studies, and in some cases preliminary clinical evidence as well,
support other possible therapeutic applications of echinacea preparations (e.g.,
immunostimulant, anti-infective, wound-healing) [75]. However, due to the limited data, the actual therapeutic outcome is
inconclusive.

Adverse Effects and Drug Interactions

In clinical trials, echinacea preparations are generally
well tolerated, and the number of patients dropping out of studies is similar to the
placebo group. A single study conducted in children 2 to 11 years of age reported the
occurrence of an allergic rash [183]. In
adults, one review found that the most common adverse effects were nausea and vomiting
(<1%), abdominal pain (<1%), and mild drowsiness and headache (<1%) [31]. One case of anaphylaxis has been
reported in a patient with a history of atopic reactions [184]. Echinacea should not be administered to
individuals with allergies to other plants of the Asteraceae family, including daisies, ragweed, marigolds, and
chrysanthemums. It is also recommended to avoid echinacea if currently on
immunosuppressants [75].

Toxicology

Both in vitro and in vivo studies suggest that, even
when administered at doses several-fold higher than the ones normally used, echinacea is
devoid of toxicity. Analysis of 112 pregnant women who were exposed to echinacea
preparations during the first trimester of pregnancy showed no difference in fetal health
when compared to the nonechinacea-exposed group [185]. Although other studies seem to confirm safety, echinacea preparations
should be avoided during the first trimester due to lack of definitive evidence.

Dosage

For treatment of cold symptoms and upper respiratory infections, an initial 300–1000
mg titrated dose of powdered herb in capsules or its equivalent (tincture or juice) is
administered for 5 to 7 days [31,49,124,156]. Use for more
than 8 weeks at a time should be avoided because of the potential for immunosuppression
[75]. Preparations containing 15%
pressed herb are used topically as disinfectants.

KAVA

Efficacy: ★★★E

Safety: AEs/DIs/UnS

Common Name and Scientific Name

Kava (Piper methysticum), a member of the pepper
family, is a widely cultivated shrub indigenous to the South Pacific islands. It is also
known as kava-kava, kawa, or ava pepper [75].

Historical and Current Use

A drink prepared from the root of the kava plant has been used traditionally in the
South Pacific for ceremonial, social, and medicinal purposes for several centuries, if not
millennia. It is used for its mild relaxing and calming properties, culturally comparable
to alcohol use in Western societies. Following the European trend, the use of kava for the
treatment of anxiety has become popular in the United States. In some countries, including
Germany, it has been commonly prescribed to treat anxiety, stress, and insomnia, although
very serious concerns regarding potential hepatotoxicity have led to warnings and bans in
North America.

Pharmacology

The lipid-soluble extract of kava is rich in kava
pyrones, including kavain, dihydrokavain, and methysticum [186]. Kava pyrones block voltage-dependent
sodium channels, a mechanism responsible for the local anesthetic properties of kava
drinks, which causes numbness and tingling of the mouth. Kava also contains antioxidant
flavonoids and alkaloids. It has been reported that kava has a direct effect on limbic
structures, particularly the amygdala. It does not bind to the gamma-aminobutyric acid
(GABA)A receptors, unlike benzodiazepines, which target the GABAA receptors abundantly
distributed in the cerebral cortex. This may account for the difference in anxiolytic
properties of kava, which, unlike benzodiazepines, does not cause sedation [187].

At higher doses, kava lactones also have muscle-relaxant and anticonvulsant
properties, which are possibly related to the stimulation of the glycine receptor [188]. Kavain has dose-dependent antiplatelet
aggregation and anti-inflammatory properties [189].

Evidence-Based Therapeutic Use and Effectiveness

A Cochrane Review found that, compared with placebo, kava extract is
an effective symptomatic treatment for anxiety, although, at present, the size of the
effect seems small. The effect lacks robustness and is based on a relatively small
sample. The data available from the reviewed studies suggest that kava is relatively
safe for short-term treatment (1 to 24 weeks), although more information is
required.

The clinical effectiveness of kava has been widely studied, and clinical studies
strongly support its efficacy in the treatment of moderate and mild cases of anxiety. One
meta-analysis included data from 11 double-blind, controlled clinical trials, and the
authors concluded that kava, when compared to placebo, is effective in the symptomatic
treatment of anxiety [190]. A standardized
preparation of kava (LI 150) was as effective as the anxiolytic drugs buspirone and
opipramol [191,192]. An extensive literature review also
confirmed the clinical effectiveness of kava preparations in the treatment of anxiety
[31].

Several clinical studies assessed the effect of kava on memory and compared it with
both the anxiolytic oxazepam and placebo [187]. The studies concluded that kava, unlike oxazepam, does not impair
cognitive performance and memory. In fact, an improvement in memory was observed in the
kava-treated group, but these interesting results wait for confirmation [31].

Adverse Effects and Drug Interactions

In clinical trials, the side effects of kava
preparations were rare and mild, with gastrointestinal discomfort, restlessness, headache,
and dizziness reported in about 2% of patients. Kava dermatitis, a yellow discoloration of
the skin accompanied by scaly dermatitis, is only observed in chronic heavy kava drinkers
and reverses after discontinuation of kava administration. This skin condition resembles
pellagra but is resistant to niacin treatment [75]. Neurotoxicity, pulmonary hypertension, and choreoathetosis have also
been reported in chronic heavy drinkers in the Australian Aboriginal population [193]. A few rare cases of kava-induced
Parkinson-like extrapyramidal disorders have been reported, as well as the aggravation of
existing Parkinson's disease in one patient and one case in the United States of
rhabdomyolysis related to the ingestion of a large amount of kava [49,192]. There are some reports suggesting that kava may cause severe and, in
some cases, irreversible liver damage. As a result, the FDA issued an advisory letter to
healthcare professionals stating possible health risks [194]. In August 2002, Health Canada issued a stop-sale order for all
products containing kava [195].

Kava extracts interact with and potentiate the effects
of anxiolytic and depressant drugs, such as benzodiazepines, barbiturates, and alcohol.
Due to its antiplatelet properties, kavain-containing preparations should not be
administered to patients undergoing anticoagulant therapy, although the clinical relevance
of this potential interaction has not been established. Kava preparations should also be
avoided in patients with extrapyramidal disorders, including Parkinson's disease. Finally,
due to the potential hepatotoxicity, kava should not be administered to patients with
liver disease or those treated with potentially hepatotoxic medications such as
acetaminophen, anabolic steroids, or the anticancer agent methotrexate [31,75,196]. As a
precautionary measure, kava should not be administered during pregnancy and lactation due
to the lack of safety studies [75]. Kava
administration should be discontinued at least 24 hours prior to surgery because of
possible potentiation of the sedative effect of anesthetics [197].

Toxicology

More than 30 cases of kava-induced hepatotoxicity, ranging from hepatitis and
cirrhosis to acute liver failure and death, have been reported in the literature. One
study of lipid-extractions of kava led researchers to state that rather than being caused
by directly toxic mechanisms, reactions to kava likely stemmed from immunologically
mediated idiosyncratic mechanisms; therefore, the hepatotoxicity of kava may be similar to
benzodiazepines [198]. An Australian trial
concluded that water-extracted kavalactones, using dried roots sourced from the island of
Vanuatu and prepared in a controlled pharmaceutical manufacturing facility, caused neither
an increase in liver enzymes nor hepatotoxic symptoms [199]. Other studies have shown that kava suppresses CYP450 enzymes in the
liver, leading to hepatotoxic concentrations of concurrently administered drugs [200]. Although no cases of hepatotoxicity
were reported in any of the clinical trials included in a Cochrane Review, it is not
recommended for use in the United States [124,190].

Dosage

Standardized products are available, and the usual recommended daily dose of
kavalactones ranges from 120–250 mg/day, divided in 2 to 3 equal doses [31,49]. In the United States, most formulations are standardized to 30% or
55%, meaning that a 100 mg tablet contains 30 mg or 55 mg of kavalactones, respectively.
Usually, kava use should be limited to 3 months to avoid potential habituation, and
patients should be advised of the potential adverse effects on motor coordination and
capacity to drive or operate heavy machinery [49].

GARLIC

Efficacy: ★★E

Safety: AEs/DIs

Common Name and Scientific Name

Garlic (Allium sativum), also known as allium, is
related to chives (Allium schoenoprasum) and onions
(Allium cepa), and all belong to the Liliaceae
family, which also includes lilies.

Historical and Current Use

The recorded medicinal use of garlic goes back to ancient Egyptian, Greek, and Roman
civilizations. It was used for the treatment of a variety of conditions, including heart
problems, headaches, intestinal parasites, and tumors, and as a local disinfectant. In the
nineteenth century, Louis Pasteur also reported the antimicrobial properties of garlic. It
is now used for its effectiveness in reducing cholesterol and for its antithrombotic and
antioxidant properties, as well as for its ability to lower blood pressure. Together,
these properties have also provided some support for the use of garlic in the prevention
of cardiovascular diseases, including atherosclerosis [31,35,49]. The benefits of garlic in the treatment
of certain cancers, specifically stomach and colorectal, have also been investigated [201].

Pharmacology

The beneficial effects of garlic have been related to its sulfur compounds. More than
20 different sulfur compounds have been identified in garlic. The sulfur compound allinin
(S-allyl-l-cysteine sulfoxide) is transformed to allicin (diallyl thiosulfinate) via the
enzyme alliinase when the bulb is crushed or ground. Allicin is an unstable molecule that
is converted into more stable compounds. Other sulfur compounds, such as peptides,
steroids, terpenoids, flavonoids, and phenols, derive from allicin metabolism and have
been the subject of investigations aimed at identifying their biological role [202]. In vitro and in vivo studies have
associated allicin with the antibacterial properties of garlic. Commercially available
garlic extracts are standardized to the allicin content. Three water-soluble allicin
derivatives, s-allylcysteine (SAC), s-ethylcysteine (SEC), and s-propylcysteine (SPC), are
the most effective in reducing in vitro cholesterol synthesis in hepatocytes by 42% to 55%
[203].

Methyl-allyl trisulfide (MATS), a lipid-soluble allicin derivative, inhibits
cyclooxygenase activity and prostaglandin synthesis and is responsible for the
antithrombotic and antiplatelet aggregation properties of garlic [204]. Another sulfur compound, diallyl
trisulfide (DATS), is a potent inhibitor of colon and lung human cancer cell proliferation
in cell cultures and is at least partially responsible for the anticancer properties of
garlic [205,206,207,208].

The antioxidative properties of garlic are exerted indirectly through the sulfur
compound-induced stimulation of protective antioxidant enzymes present in the body,
including glutathione-S-transferase, superoxide dismutase, and catalase [35,204].

Evidence-Based Therapeutic Use and Effectiveness

The American Dietetic Association asserts that consumption of garlic
may or may not be beneficial for the reduction of blood pressure, as the current
evidence is inconclusive regarding its effect on blood pressure.

Level of Evidence: III (Studies of
weak design for answering the question or inconclusive findings due to design flaws,
bias, or execution problems)

Several clinical trials have reported that garlic lowers
total cholesterol levels by 8% to 15% [209,210]. This effect results from the
lowering of the low-density lipoprotein (LDL) and triglycerides, while the high-density
lipoprotein (HDL) values remained unchanged. A meta-analysis confirmed that, after 10 to
12 weeks, garlic lowers plasma cholesterol, although the benefits (4% to 6%) were less
pronounced than previously reported, and this effect was not statistically significant
after a six-month period [211]. In 2001,
an extensive meta-analysis of 34 randomized clinical trials including almost 2000 patients
confirmed the previous assertions [212].
In conclusion, garlic preparations are moderately effective in lowering LDL and
triglycerides and do not change the HDL concentration in the plasma [31].

The effects of garlic on blood pressure have been
studied in several clinical trials. Most studies have shown a small (6%) yet statistically
significant effect, although these findings were not replicated by other studies [31]. Garlic is not recommended for the
management of hypertension [75,213].

Garlic has also been shown to inhibit platelet
aggregation, as expected by its inhibitory effects on cyclooxygenase and prostaglandin
synthesis. The effective dosages are not well established, and comparison with other
antiplatelet aggregation drugs is not yet available. Because several reports have
associated garlic with bleeding accidents, administration should be limited to lower
dosages and co-administration with drugs that affect hemostasis, including antiplatelet
aggregation drugs (e.g., aspirin) or anticoagulants (e.g., warfarin), should be avoided
[31,130].

Some clinical studies suggest that garlic preparations slow the progression of
atherosclerotic plaques [214]. Although
encouraging, these results are preliminary and further studies are required [75].

The anticancer properties of garlic compounds have been
reported both in vitro and in vivo, but their clinical effectiveness remains to be
established. Epidemiological studies suggest that regular consumption of garlic may be
associated with a lower risk of developing gastric and colorectal malignancies [215]. Although the evidence is cautiously
positive, well-designed clinical trials are needed before a conclusion can be
reached.

Adverse Effects and Drug Interactions

The most common adverse effects reported are bad breath
and body odor [75]. Less commonly,
dyspepsia and flatulence are also reported. In rare cases, dermatitis and respiratory
difficulty can occur in hypersensitive patients [49]. The highest risk of herb-drug interaction is between garlic and
anticoagulant drugs, such as the vitamin K inhibitor warfarin, and antiplatelet
aggregation agents such as ticlopidine and clopidogrel and results from the
pharmacodynamic potentiation of mechanisms of action [130].

Toxicology

Garlic preparations administered within the recommended dosages are safe, although
they should not be administered to patients allergic to garlic or to other members of the
Liliaceae family, namely chives, onions, leek, or lilies [31,75,130]. A dangerous
pharmacokinetic interaction between garlic and the protease inhibitor saquinavir has been
reported, as it reduces the plasma concentration of the anti-HIV drug by 50% [216].

Dosage

Administration of garlic preparations varies greatly according to the preparation used
(i.e., fresh, powder, oil extracts). Standardized preparations to 1.3% allinin or 0.6%
allicin are usually administered at 600–900 mg per day. This is considered equivalent to
one small clove of fresh garlic [49].

VALERIAN

Efficacy: ★★E

Safety: S

Common Name and Scientific Name

Valerian (Valeria officinalis), also known as
baldrian, is a member of the Valerianaceae family.
Other species of the same family that are also used for medicinal purposes include
V. wallichi and V.
sambucifolia.

Historical and Current Use

Historical documents from ancient Greece, China, and
India widely report the use of preparations from valerian root and rhizome in the
treatment of insomnia and anxiety. This herb, native to Asia and Europe, is found
throughout the world. Topically, it has been used in the treatment of acne and wound
healing. It has also been used traditionally for the treatment of a variety of disorders,
including digestive problems, flatulence, congestive heart failure, urinary tract
disorders, and angina pectoris. For the past 200 years, valerian has been widely used in
Europe and North America for its mild sedative properties [35,49].

Pharmacology

A large number of chemicals, including monoterpenes, sesquiterpenes, valepotriates,
amino acids, and alkaloids, have been extracted from valerian. Although no single
component has been shown to account for its pharmacological properties, the biologically
active valerenic acid has been used as the constituent for standardization. In vivo
studies have confirmed the sedative, anxiolytic, and anticonvulsant properties of valerian
preparations. Studies have also shown the agonistic effect of valerian and some of its
individual compounds on the GABA(A) receptors and on the 5-HT5a serotonin receptors [217,218,219]. Other studies
have revealed that valerian extracts inhibit the presynaptic GABA carrier, further
contributing to an increased GABAergic inhibitory activity in the brain [220]. Valerenic acid also inhibits GABA
transaminase, the enzyme responsible for GABA metabolism [221]. Together, these findings contribute to
a better understanding of the molecular mechanisms underlying the sedative and
anticonvulsant properties of valerian. More recently, research has identified valerenic
acid and its modulation of the GABA(A)-ergic system as probable cause of the anxiolytic
effects, a mechanism similar to benzodiazepines (e.g., diazepam) [222].

Evidence-Based Therapeutic Use and Effectiveness

A systematic review of 9 randomized clinical trials
found that results regarding the effectiveness of valerian in the treatment of insomnia
were inconclusive [223]. Some benefits
were reported within 1 to 2 days, but benefits on sleep were observed only after 4 weeks
of treatment. A larger European clinical trial reported that the valerian had minimal or
no effect on sleep regulation [224].
Unfortunately, patients were treated for only 2 weeks, a time period considered too short
when compared with previous studies, which may account for the negative outcome.

No well-designed trials of valerian in the treatment of anxiety in humans have been
published to date. An investigation of the effect of valerenic acid on rats concluded that
valerian use was related to a reduction of anxious behavior [222].

Adverse Effects and Drug Interactions

In clinical trials, valerian side effects were minor, most commonly headache, stomach
upset, or dizziness, and were usually reported as frequently as in the placebo group.
Adverse effects on reaction time and alertness were much lower than benzodiazepines.
Dependence and withdrawal have not been reported in any of the clinical trials, although a
single case report of withdrawal symptoms after discontinuation has been published [225]. As valerian and benzodiazepines
similarly target the GABAA receptor, it is possible that the patient may develop physical
dependence after lengthy administration. It is therefore advisable to discontinue valerian
administration progressively. Valerian potentiates the effects of other sedatives, such as
benzodiazepines, barbiturates, alcohol, kava, and chamomile, and should not be
co-administered in conjunction with these drugs or phytomedicines [31].

Toxicology

Valerian is considered safe by the FDA, but administration during pregnancy and
breastfeeding is not advised due to the limited availability of safety data [75].

Dosage

In clinical trials, for the treatment of insomnia, 900 mg of a standardized solution
equivalent or 1.5–3 grams of dried root was administered 30 minutes to 1 hour before
bedtime [49]. Valerian extract, in doses
of 400–600 mg, has been used in clinical trials evaluating valerian in insomnia [226,227].

ANDROGRAPHIS

Efficacy: ★★E

Safety: AEs/DIs

Common Name and Scientific Name

Andrographis (Andrographis paniculata) is also
known as Justicia paniculata, green chiretta, king of
bitters, kan jang, and sambiloto. It is an herb naturally found in Asia, including India,
Southeast Asia, and southern China, and it is also cultivated for commercial use in the
preparation of traditional HMs. Andrographis is an annual tall herb, up to one meter high,
with small white flowers. It thrives in humid climates and shady areas.

Historical and Current Use

The bitter-tasting leaves of andrographis have been used for centuries in traditional
Indian and Chinese medicine in the preparation of an infusion used for the treatment of
digestive ailments and fever. In Malaysia, andrographis has also been traditionally used
for the treatment of hypertension [228].
In northern European countries, andrographis is used for the prevention of upper
respiratory tract infections [31].

Pharmacology

Andrographis is rich in diterpenoids and flavonoids. At least 9 diterpenoids,
including andrographolide, 14-deoxyandrographolide (DA), and
14-deoxy-11-oxoandrographolide (DDA), have been isolated.

Evidence-Based Therapeutic Use and Effectiveness

Several clinical trials, including almost 900 subjects, have assessed the
effectiveness of andrographis in the treatment and prevention of upper respiratory tract
infection. Two meta-analyses concluded that andrographis was significantly more effective
than placebo for the treatment of upper respiratory tract infection symptoms [230,231]. Limited evidence also suggests that andrographis preparations may be
effective in the prevention of upper respiratory tract infection [232,233]. Two clinical studies concluded that andrographis is also effective in
the treatment of influenza symptoms, although larger and better-designed studies are
needed to confirm the results [31].

Adverse Effects and Drug Interactions

Andrographis is considered safe and well tolerated. Headache, nausea, vomiting,
abdominal discomfort, and nasal congestion are the most commonly reported adverse effects
[31,75]. Although data regarding andrographis interactions with other drugs is
still limited, due to andrographis' hypotensive and hypoglycemic properties, concurrent
administration with antihypertensive and hypotensive drugs should be avoided.

Toxicology

In clinical trials, a dose-response dependent toxicity of andrographis has been
identified, and fatigue, headache, and lymphadenopathy have been described [232,234,235]. Three cases of
anaphylactic reaction have also been reported [230].

Dosage

Three hundred milligrams of standardized preparations of
andrographis (4% andrographolides) are taken 4 times a day, for as long as 2 weeks [31].

ENGLISH IVY LEAF

Efficacy: ★★★E

Safety: S

Common Name and Scientific Name

English ivy (Hedera
helix), also known as common ivy, is an evergreen climbing vine. It is native
to Europe and Central Asia, grows easily, and is commonly found in humid environments and in
forests. It is often used for decorative purposes. It is different from ground ivy
(Glechoma hederacea) and American ivy (Parthenocissus quinquefolia). It is particularly important not to
confuse it with poison ivy (Rhus toxicodendron).

Historical and Current Use

The glossy and dark green leaves of common ivy have been
traditionally used for the treatment of a wide variety of disorders, including respiratory
disease, arthritis, fever, burns, and infections. It is now used as an expectorant and in
the treatment of bronchitis and asthma [49].

Pharmacology

Ivy leaves are rich in saponins (e.g., hederin, hederacoside) but also contain
sterols, flavonol glycosides, and polyalkenes among other chemicals. Saponins stimulate
secretion of mucus in the upper respiratory tract and have a mucokinetic and mucolytic
effect [186]. They also prevent
acetylcholine-induced bronchospasm [236].
Hederacoside C has antifungal and antibacterial properties [172]. Together, these bronchodilatory and
antimicrobial properties of ivy leaf extracts provide the pharmacological evidence to
support their beneficial effects in the treatment of upper respiratory tract
infections.

Evidence-Based Therapeutic Use and Effectiveness

The clinical efficacy of ivy leaf extracts has been the
subject of one meta-analysis [237]. Five
clinical trials, three of which measured its effect on children, indicated that the
treated group showed an improvement in chronic bronchial asthma. In another study not
included in the previous review, 1350 children with chronic bronchitis were treated with
standardized ivy leaf extracts for 4 weeks. A significant improvement or cure of the
following symptoms was observed, when compared to the baseline: cough (92%), expectoration
(94%), dyspnea (83%), and respiratory pain (87%) [238]. A postmarketing study of almost 10,000 patients with bronchitis
showed that, after a 7-day treatment with ivy leaf extracts, 95% of the patients had
improved significantly [239].

Adverse Effects and Drug Interactions

Ivy leaf extracts are generally considered safe. Mild adverse effects, such as
gastrointestinal discomfort, eructation, or nausea, are observed in 0.2% to 2.1% of
patients [238,239]. No drug interactions have been
reported. Considering the detergent-like actions of saponins, it has been suggested that
ivy leaf extracts should not be ingested at the same time as other drugs, considering the
unlikely possibility that ivy leaf extracts may facilitate the absorption of the other
drugs. However, this warning is not supported by any evidence and should be considered as
speculative.

Toxicology

Ingestion of ivy berries can be toxic, and falcarinol present in cut ivy leaves may
cause contact dermatitis, particularly in sensitive individuals [130]. In a bizarre case, ingestion of ivy
leaves caused mechanical obstruction and suffocation [240]. Toxicological tests confirmed the cause of death as being
suffocation, and no toxin was detected in cardiac blood, femoral blood, or urine of the
deceased [240].

It has been suggested that ivy leaf products should be avoided during pregnancy
because the emetine content in ivy leaf may cause uterine contractions [241]. Data on the effects of ivy leaf
extracts during lactation are not yet available, and as a result, ingestion of ivy leaf
extracts in these cases should be avoided.

PEPPERMINT

Efficacy: ★★E

Safety: S

Common Name and Scientific Name

Peppermint (Mentha x piperita
Lamiaceae) is a hybrid of Mentha spicata
Lamiaceae (spearmint) and Mentha aquatic
L. of the Lamiaceae (mint) family. It is
also known as peppermint oil, menthol, mint, balm mint, brandy mint, and green mint. The
plant is native to Europe but is widely cultivated in the United States and Canada [75,244].

Historical and Current Use

Peppermint leaf and peppermint oil have a history of use
for digestive orders that dates back to ancient Egypt. The plant was first described in
England in 1696, and both the leaf and the oil have been used in Eastern and Western
traditional medicine as antispasmodics, aromatics, and antiseptics. Peppermint oil is used
in herbal remedies, cosmeceuticals, personal hygiene products, foods, and pharmaceutical
products. Topical preparations have traditionally been used to calm pruritus and relieve
irritation and inflammation [244,246,247,248,249,250]. Peppermint oil is widely used as a spasmolytic agent in irritable
bowel syndrome (IBS) [250,251,252].

Evidence-Based Therapeutic Use and Effectiveness

Irritable Bowel Syndrome

The clinical effectiveness of peppermint oil in the treatment of IBS has been
extensively studied. A Cochrane review of clinical studies that evaluated the efficacy of
bulking agents, antispasmodics (e.g., peppermint oil), and antidepressants for the
treatment of IBS was published in 2013 [255]. The review included 56 randomized controlled trials published between 1966 and 2009
involving 3,725 patients with IBS who were older than 12 years of age. The primary
outcomes evaluated were improvements of abdominal pain, global assessment, and symptom
score. Both antidepressants and antispasmodics demonstrated improvement in outcome
measures. Abdominal pain improved in 58% of antispasmodic patients compared to 46% with
placebo. Global assessment showed 57% improvement in patients taking antispasmodics
compared to 39% with placebo; and 37% of patients taking antispasmodics showed improved
symptom score compared to 22% with placebo [255]. A subgroup analysis of different types of antispasmodics, including
peppermint oil, revealed statistically significant benefits [255]. Evidence suggests that enteric-coated
peppermint oil may be effective in relieving some of the symptoms of IBS [75,250,256].

Dyspepsia

The use of peppermint in combination with other herbals for treatment of functional
dyspepsia in adults and children has been reviewed in the literature [257,258,259,260]. A study published in 2000 evaluated the
safety and effectiveness of enteric-coated capsules containing a fixed combination of 90
mg peppermint oil and 50 mg caraway oil [258]. The study included 96 patients who received either one capsule twice
daily or placebo for 28 days. Outcomes measured included change in pain intensity, change
in sensation of pressure, heaviness and fullness, and global improvement as rated by the
investigators. On the 29th day, the average intensity of pain was reduced by 40% with
peppermint use, compared with 22% with placebo; pressure, heaviness, and fullness was
reduced by 43%, compared with 22% with placebo; and 67% of patients were very much
improved, compared with 21% with placebo.

A choleretic action of peppermint oil has been described, with possibly applicability
in the management of gallstones [75,250]. Its antispasmodic action makes it
useful in patients with colonic and esophageal spasm and in endoscopy [262,263,264,265,266].

Adverse Effects and Drug Interactions

Menthol, the major component of peppermint oil, may cause contact dermatitis in some
individuals. Mucosal burns and swelling of the tongue and oral cavity have been reported
following ingestion of peppermint oil. Other reported incidences include stomatitis,
vulval allergic contact; however, such reactions appear to be rare [75,267,268,269,270].

Toxicology

Peppermint is generally recognized as safe. Comprehensive reports on its safety have
identified the constituents pulegone and menthofuran as being of toxicologic concern [271,272].

Dosage

Doses of peppermint oil of up to 1200 mg in enteric-coated tablets are used to treat
IBS [75]. The tablets should be swallowed
whole, not crushed, broken, or chewed, to avoid irritation to the mouth, esophagus, and
stomach, and they should be taken 30 to 60 minutes prior to meals on an empty stomach
[75,264,273]. Doses of
0.1–0.24 mL of peppermint oil have been used as a carminative in clinical studies [75,255,274,275].

GINGER

Efficacy: ★★★E

Safety: S

Common Name and Scientific Name

Ginger (Zingiber capitatum,
Zingiber officinale) is also known as black ginger, ginger root, and
zingiberis rhizoma. Ginger is native to tropical Asia and is a perennial that is
cultivated in Australia, Brazil, China, India, Jamaica, West Africa, and parts of the
United States. The rhizome is used both medicinally and as a culinary spice [75].

Historical and Current Use

The medicinal use of ginger dates back to ancient China and India. It is referred to
in Chinese pharmacopeias, Ayurvedic medicine scriptures, and Sanskrit writings. Its
culinary properties were discovered in the 13th century, leading to its widespread use in
Europe. Apothecaries in the Middle Ages recommended ginger for travel sickness, nausea,
hangovers, and flatulence. Other uses include for the common cold, fever, sore throat,
gastrointestinal complications, and indigestion. Ginger is referenced in the official
pharmacopeias of more than a dozen countries. It is approved by Germany's Commission E for
indigestion and to help prevent motion sickness. In the United States, ginger is approved
as a dietary supplement and commonly used as a treatment for nausea [75,246,276,277].

Pharmacology

Only unbleached ginger is a medicinal-grade drug, containing 1.5% or more volatile
oil. More than 400 different compounds have been identified in ginger. The major
constituents are carbohydrates (50% to 70%), which are present as starch. Amino acids, raw
fiber, protein, phytosterols, vitamins and minerals are among the other constituents.
Gingerols, a class of structurally related compounds, form shogaols, the pungent
constituents of ginger. The primary shogaols are (6)-gingerol and (6)-shogaol [75,278,279]. Ginger exerts in
vitro antioxidative, antitumorigenic, and immunomodulatory effects and is an effective
antimicrobial and antiviral agent [279].

Evidence-Based Therapeutic Use and Effectiveness

Clinical trials in humans have examined the antiemetic effects of ginger as they
relate to nausea of various etiologies (e.g., motion sickness, postoperative,
pregnancy-related, chemotherapy-related). In particular, ginger has been found to be more
effective than placebo in controlling pregnancy-related nausea and vomiting in randomized
controlled trials. The mechanism by which this occurs is unclear, but enhanced
gastrointestinal transport, antiserotonin activity, and possible central nervous system
effects have been described in animal studies [75]. Although ginger has been shown to be effective in ameliorating
pregnancy-related nausea and vomiting, its safety during pregnancy has not been
established.

Adverse Effects and Drug Interactions

Ginger may enhance the adverse/toxic effect of agents with anticoagulant/antiplatelet
properties; bleeding may occur [75].
Adverse reactions reported in trials are uncommon [75]. Case reports of arrhythmia and IgE allergic reaction have been
documented [277,286].

Toxicology

Because there is little data on the toxicity of ginger in humans, most authorities
agree that its use during pregnancy and lactation should be avoided due to the lack of
data on fetal outcomes [75].

Dosage

Ginger has been used in clinical trials in doses of 250 mg to 1 g, repeated three to
four times daily [75].

SOY

Efficacy:★E

Safety:No S data

Common Name and Scientific Name

Soy (Glycine max), a plant in the pea family, is
also known as soy isoflavones, soya, and soybean. Soy is a common source of dietary
phytoestrogens found in American diets as either a food or a food additive [75,244,300].

Historical and Current Use

Traditional and folk uses of soy products include for menopausal symptoms,
osteoporosis, memory problems, high blood pressure, high cholesterol, and breast and
prostate cancer. Soy may be taken as a dietary supplement. Some studies suggest that daily
intake of soy protein or soy isoflavones supplements may reduce LDL cholesterol and
menopausal symptoms (e.g., hot flashes) in women; however, not enough evidence exists to
determine whether soy supplements are effective for any other health uses [300].

Pharmacology

The isoflavones in soybean (i.e., genistein, daidzein, glycitein) have a chemical
structure similar to estrogen. They bind to both estrogen receptors (ER alpha and ER beta)
and exert estrogen-like effects under some experimental conditions [299]. Genistein, daidzein, and glycitein
undergo metabolism to the isoflavandiols, equol, and p-ethylphenol. The metabolism is
highly variable (i.e., dependent upon the effect of carbohydrate intake on intestinal
fermentation). The isoflavones are secreted into bile via the enterohepatic circulation
and eliminated in urine [75].

Evidence-Based Therapeutic Use and Effectiveness

Although soy protein has gained considerable attention for its potential role in
improving risk factors for cardiovascular disease, the American Heart Association (AHA)
and an expert panel from the American College of Cardiology (ACC) found that the evidence
of benefit is uncertain, with a relatively small decrease (3%) in LDL cholesterol
concentrations and no effect on other lipid risk factors with soy protein consumption, as
compared with milk or other proteins [294].

To assess the effectiveness of phytoestrogens, including soy and soy extracts, for
reducing hot flushes and night sweats in postmenopausal women, the authors of a Cochrane
review evaluated the results of 30 randomized trials that had a duration of at least 12
weeks and in which the intervention for symptom relief was the use of a food or supplement
with high levels of phytoestrogens [292].
However, a strong placebo effect was reported in most of the trials, with a reduction in
symptom frequency ranging from 1% to 59%. The authors of the review found no evidence of
effectiveness with phytoestrogen use for relief of menopausal symptoms. Authors of other
studies confirm this conclusion [290,291].

Several meta-analyses of clinical trials have evaluated the effectiveness of soy
preparations in protecting against decreases in bone mineral density (BMD). Some report
small improvements in BMD; others report no effect [295,296].

Adverse Effects and Drug Interactions

Soybeans and soy products, including supplements, are generally well tolerated.

Toxicology

Concern has been expressed that feeding infants soy formula may adversely affect
development of the reproductive system due to the estrogen-like activity of isoflavones;
however, data is inconclusive to permit a firm conclusion [289].

Dosage

The effects of daily doses (40–120 mg) of isoflavones for a variety of conditions have
been studied in a large number of clinical trials [75]. A dose of 20–106 g soy protein taken daily by mouth has been studied
in individuals with high cholesterol. Isoflavones content has ranged from 60 mg to more
than 100 mg daily [288].

Historical and Current Use

C. nobilis is a slow-growing perennial; M. recutita grows as an upright annual. The fragrant flowering
heads of both plants are collected and dried for use as teas and extracts [75]. Both plants have been used since Roman
times as antispasmodics and sedatives in the treatment of digestive and rheumatic
disorders and as a wash to cleanse wounds and ulcers. Various formulations have been used
to treat colic, cystitis, fever, flatulence, and vomiting [285,287]. German chamomile flower is approved by the German Commission E for
use as an inhalant in skin and mucous membrane inflammations, bacterial skin diseases
(including those of the oral cavity and gums), and respiratory tract inflammations and
irritations. It is also the variety most commonly used in the United States. The flower is
approved for use in baths, as irrigation for anogenital inflammation, and for internal use
to treat gastrointestinal spasms and inflammatory diseases [284]. M.
recutita is widely used in Europe as a botanical for wound care. Aqueous
extracts are used as washings or wet packs for fresh wounds. Alcoholic extraction yields
the most complete blend, which can be transferred to aqueous formulations or ointments
[281]. In Europe, traditional
phytomedicines such as chamomile play an adjuvant role in acne therapy, either in addition
to or in combination with intensive cosmetic care. After cleaning, creams or aqueous
decoctions are applied topically [278].

Pharmacology

The chemical compounds of C. nobilis and M. recutita are similar. Chamomile tea, brewed from dried
flower heads, contains 10% to 15% of the plant's essential oil. The blue-colored volatile
oil is a complex mixture of sesquiterpenes, sesquiterpene lactones, and acetylene
derivatives. Phenolic compounds found in the flowers include hydroxycinnamic acid
derivatives, caffeic acid, and flavonoids (i.e., apigenin, luteolin, chamaemeloside). A
novel and potent NK1 receptor antagonist has been identified in Matricaria flowers. Coumarin has also been identified [75]. The chemical constituents of chamomile
(e.g., bisabolol, chamazulene) and the flavonoids apigenin and luteolin possess
anti-inflammatory properties. Apigenin has also been shown to reversibly inhibit
irritant-induced skin inflammation in animals and to exert antispasmodic effects in the
intestines [293]. Bisabolol and the
flavonoids have demonstrated antispasmodic effects [75].

Evidence-Based Therapeutic Use and Effectiveness

The chemical components in chamomile (i.e., bisabolol, flavonoids) have demonstrated
antispasmodic effects in animal experiments. Chamomile infusions have been used
traditionally as gastrointestinal antispasmodics despite the lack of rigorous trials to
support this use [75]. Commercial
preparations of creams containing chamomile are also widely available despite the paucity
of trials to support their use [297,301].

It has been suggested that chamomile might provide clinically meaningful
antidepressant activity [298]. The authors
of a Canadian study examined whether commercially available botanicals directly affect the
primary brain enzymes responsible for GABA metabolism [283]. Approximately 70% of all extracts tested showed little or no
inhibitory effect. However, both M. recutita and
Humulus lupulus (hops) showed significant inhibition
of GAD enzyme activity in animals.

Adverse Effects and Drug Interactions

Allergic reactions to chamomile are commonly reported
and may be dependent on the route of ingestion. Hypersensitivity reactions include
anaphylaxis, dermatitis, gastrointestinal upset, lacrimation, and sneezing. The dried
flowering heads may induce vomiting in large amounts. Eye drops containing chamomile have
caused allergic conjunctivitis [75].
Chamomile may potentiate the anticoagulant effects of warfarin. No coagulation disorders
have been reported, but close monitoring of patients on anticoagulants is advised. In
vitro, chamomile has been shown to be bactericidal to some Staphylococcus and Candida species [282]. Chamomile is considered safe by the
FDA, but it should be used with caution in individuals who are allergic to ragweed, as
cross-allergenicity may occur. Symptoms include abdominal cramping, tongue thickness,
tight sensation in the throat, angioedema of the lips or eyes, diffuse pruritus,
urticaria, and pharyngeal edema [261,280].

Toxicology

Bisabolol toxicity in animal studies is reported to be low following oral
administration with no noted teratogenic or developmental abnormalities [75].

Dosage

Because of the sedative effects of chamomile, caution should be used in conjunction
with medications with sedative side effects or with alcohol. The oral dose is 400–1600
mg/day in divided doses, standardized to 1.2% apigenin per dose. Chamomile is commonly
consumed as a tea for its calming effect. It can be brewed using one heaping teaspoon of
dried flowers steeped in hot water for 10 minutes and may be consumed up to three times
per day [245].

CONCLUSION

Herbal medications have become an important issue in North America for a variety of
social, economic, and medical reasons, and the use of HMs continues to increase. Data from the
National Center for Health Statistics indicates that supplement use among U.S. adults 20 years
of age and older increased from 42% to 50% during the period between 2003 and 2006, with use
more common among women than men [242].

In 2007, out-of-pocket expenditures for CAM in the United States were $33.9 billion; this
accounts for 1.5% of total national healthcare spending and 11.2% of total out-of-pocket
expenditures [243]. The cost of dietary
supplements alone was $14.8 billion, or nearly one-third of the $47.6 billion that U.S. adults
spent out-of-pocket on prescription drugs [243]. Considering the high price of health insurance and changing attitudes towards CAM, the
expenditures today are most likely greater.

In addition, more than 50% of patients receiving conventional medical care also use CAM
[9]. An estimated 50% to 70% of patients
fail to disclose the use of CAM to their healthcare providers, and concern regarding a
possible negative reaction or perceived lack of interest by the healthcare provider have been
identified as the main reasons for limited disclosure of CAM use [9,11]. It is commonly believed by the population in general, and by many
healthcare providers as well, that due to their natural origin, these products are
intrinsically safe and devoid of adverse effects or toxicity, or that the worst possible
outcome is lack of therapeutic effectiveness. This has been proven false.

It is vital that healthcare providers have an understanding of the pharmacological
properties and evidence-based therapeutic efficacy of HMs. Healthcare providers should be
aware of the need to inquire about and include current or past use of HMs in the patient's
medical history and discuss relevant information with their patients. Providers also should be
aware of the possible interactions with conventional medications and evaluate the potential
therapeutic benefits of HMs when appropriate.

RESOURCES

MedWatch: The FDA Safety Information and Adverse Event Reporting
Program

16. U.S. Food and Drug Administration. Final Rule Declaring Dietary Supplements
Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk; Small
Entity Compliance Guide. Available at http://www.fda.gov/Food/GuidanceRegulation/default.htm. Last accessed April 9,
2013.

71. Srinivasan VS. Challenges and scientific issues in the standardization of
botanical and their preparations. United States Pharmacopeia's dietary supplement
verification program: a public health program. Life Sci.
2006;78(18):2039-2043.

148. Hopfenmüller W. Evidence for a therapeutic effect of Ginkgo biloba special
extract: meta-analysis of 11 clinical studies in patients with cerebrovascular insufficiency
in old age. Arzneimittelforschung. 1994;44(9):1005-1013.

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1. American Urological Association Education and Research, Inc. Guideline
on the Management of Benign Prostatic Hyperplasia (BPH). Linthicum, MD:
American Urological Association Education and Research, Inc.; 2010. Summary retrieved from
National Guideline Clearinghouse at http://www.guidelines.gov/content.aspx?id=25635. Last accessed June 18,
2013.

2. National Collaborating Centre for Mental Health. Depression: The
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